PAI-1 gene - Revision history

Dmitry Dzhagarov: /* PAI-1 and age-related tissue fibrosis */

2023-12-12T16:18:47Z

PAI-1 and age-related tissue fibrosis

← Older revision		Revision as of 16:18, 12 December 2023
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	== PAI-1 and age-related tissue fibrosis ==		== PAI-1 and age-related tissue fibrosis ==
	Fibrosis in numerous diseases including systemic sclerosis, pulmonary hypertension, renal hypertension, cardiac hypertension, myocardial infarction (MI), alcoholic liver disease and nonalcoholic steatohepatitis (NASH) may share common mechanisms. Tissue injury causes damage of blood vessels and the extravasation of plasma proteins, including fibrinogen, which results in the formation of a fibrin clot in the surrounding interstitium. This extracellular matrix of extravasated fibrin serves as a provisional matrix, into which cells can infiltrate during the subsequent wound healing. During the formation of a granulation tissue the cells disrupt existing cell-matrix interactions and locally degrade the surrounding [[extracellular matrix]] (ECM); they migrate, proliferate, and form new capillarylike tubular structures, which become stabilized by collagen synthesis in the course of time.<ref>Barrasa-Ramos, S., Dessalles, C. A., Hautefeuille, M., & Barakat, A. I. (2022). Mechanical regulation of the early stages of angiogenesis. Journal of the Royal Society Interface, 19(197), 20220360. PMID: 36475392 PMCID: PMC9727679 DOI: 10.1098/rsif.2022.0360</ref> The temporary fibrin matrix can be degraded by plasmin, which is activated from its zymogen plasminogen by 2 types of plasminogen activators, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA).<ref>Booth, N. A. (1999). Fibrinolysis and thrombosis. Best Practice & Research Clinical Haematology, 12(3), 423-433. PMID: 10856979 DOI: 10.1053/beha.1999.0034</ref> In addition to the u-PA/plasmin system, matrix metalloproteinases (MMPs) are also involved in the degradation of the extracellular matrix.<ref>Cabral-Pacheco, G. A., Garza-Veloz, I., Castruita-De la Rosa, C., Ramirez-Acuna, J. M., Perez-Romero, B. A., Guerrero-Rodriguez, J. F., ... & Martinez-Fierro, M. L. (2020). The roles of matrix metalloproteinases and their inhibitors in human diseases. International journal of molecular sciences, 21(24), 9739. https://doi.org/10.3390/ijms21249739</ref><ref>de Almeida, L. G., Thode, H., Eslambolchi, Y., Chopra, S., Young, D., Gill, S., ... & Dufour, A. (2022). Matrix metalloproteinases: From molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacological Reviews, 74(3), 714-770. PMID: 35738680 DOI: 10.1124/pharmrev.121.000349</ref>		Fibrosis in numerous diseases including systemic sclerosis, pulmonary hypertension, renal hypertension, cardiac hypertension, myocardial infarction (MI), alcoholic liver disease and nonalcoholic steatohepatitis (NASH) may share common mechanisms. Tissue injury causes damage of blood vessels and the extravasation of plasma proteins, including fibrinogen, which results in the formation of a fibrin clot in the surrounding interstitium. This extracellular matrix of extravasated fibrin serves as a provisional matrix, into which cells can infiltrate during the subsequent wound healing. During the formation of a granulation tissue the cells disrupt existing cell-matrix interactions and locally degrade the surrounding [[extracellular matrix]] (ECM); they migrate, proliferate, and form new capillarylike tubular structures, which become stabilized by collagen synthesis in the course of time.<ref>Barrasa-Ramos, S., Dessalles, C. A., Hautefeuille, M., & Barakat, A. I. (2022). Mechanical regulation of the early stages of angiogenesis. Journal of the Royal Society Interface, 19(197), 20220360. PMID: 36475392 PMCID: PMC9727679 DOI: 10.1098/rsif.2022.0360</ref> The temporary fibrin matrix can be degraded by '''plasmin''', which is activated from its zymogen plasminogen by 2 types of plasminogen activators, '''tissue-type plasminogen activator (t-PA)''' and '''urokinase-type plasminogen activator (u-PA)'''.<ref>Booth, N. A. (1999). Fibrinolysis and thrombosis. Best Practice & Research Clinical Haematology, 12(3), 423-433. PMID: 10856979 DOI: 10.1053/beha.1999.0034</ref> In addition to the u-PA/plasmin system, matrix metalloproteinases (MMPs) are also involved in the degradation of the extracellular matrix.<ref>Cabral-Pacheco, G. A., Garza-Veloz, I., Castruita-De la Rosa, C., Ramirez-Acuna, J. M., Perez-Romero, B. A., Guerrero-Rodriguez, J. F., ... & Martinez-Fierro, M. L. (2020). The roles of matrix metalloproteinases and their inhibitors in human diseases. International journal of molecular sciences, 21(24), 9739. https://doi.org/10.3390/ijms21249739</ref><ref>de Almeida, L. G., Thode, H., Eslambolchi, Y., Chopra, S., Young, D., Gill, S., ... & Dufour, A. (2022). Matrix metalloproteinases: From molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacological Reviews, 74(3), 714-770. PMID: 35738680 DOI: 10.1124/pharmrev.121.000349</ref>

	Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.<ref>Ghosh, A. K., & Vaughan, D. E. (2012). PAI‐1 in tissue fibrosis. Journal of cellular physiology, 227(2), 493-507. PMID: 21465481 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204398/ PMC3204398] DOI: 10.1002/jcp.22783</ref><ref>Urano, T., Suzuki, Y., Iwaki, T., Sano, H., Honkura, N., & Castellino, F. J. (2019). Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis. Current drug targets, 20(16), 1695-1701. PMID: 31309890 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696651/ PMC7696651] DOI: 10.2174/1389450120666190715102510</ref><ref>Sillen, M., & Declerck, P. J. (2021). A narrative review on plasminogen activator inhibitor-1 and its (patho) physiological role: to target or not to target?. International journal of molecular sciences, 22(5), 2721. PMID: 33800359 PMCID: PMC7962805 DOI: 10.3390/ijms22052721</ref> PAI-1 is the main inhibitor of uPA (urokinase-type plasminogen activator, fibrin-independent serine protease responsible for the activation of plasminongen to plasmin <ref>Lin, H., Xu, L., Yu, S., Hong, W., Huang, M., & Xu, P. (2020). Therapeutics targeting the fibrinolytic system. Experimental & molecular medicine, 52(3), 367-379. PMID: 32152451 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156416/ PMC7156416] DOI: 10.1038/s12276-020-0397-x</ref>) and tPA (Tissue plasminogen activator, a fibrin-dependent enzyme primarily involved in dissolving blood clots<ref>Rakic, J. M., Maillard, C., Jost, M., Bajou, K., Masson, V., Devy, L., ... & Noël, A. (2003). Role of plasminogen activator-plasmin system in tumor angiogenesis. Cellular and Molecular Life Sciences CMLS, 60, 463-473. PMID: 12737307 [https://doi.org/10.1007/s000180300039 DOI: 10.1007/s000180300039]</ref>), thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively.<ref>Ismail, A. A., Shaker, B. T., & Bajou, K. (2021). The plasminogen–activator plasmin system in physiological and pathophysiological angiogenesis. International Journal of Molecular Sciences, 23(1), 337. PMID: 35008762 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745544/ PMC8745544] DOI: 10.3390/ijms23010337</ref>		Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.<ref>Ghosh, A. K., & Vaughan, D. E. (2012). PAI‐1 in tissue fibrosis. Journal of cellular physiology, 227(2), 493-507. PMID: 21465481 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204398/ PMC3204398] DOI: 10.1002/jcp.22783</ref><ref>Urano, T., Suzuki, Y., Iwaki, T., Sano, H., Honkura, N., & Castellino, F. J. (2019). Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis. Current drug targets, 20(16), 1695-1701. PMID: 31309890 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696651/ PMC7696651] DOI: 10.2174/1389450120666190715102510</ref><ref>Sillen, M., & Declerck, P. J. (2021). A narrative review on plasminogen activator inhibitor-1 and its (patho) physiological role: to target or not to target?. International journal of molecular sciences, 22(5), 2721. PMID: 33800359 PMCID: PMC7962805 DOI: 10.3390/ijms22052721</ref> PAI-1 is the main inhibitor of uPA (urokinase-type plasminogen activator, fibrin-independent serine protease responsible for the activation of plasminongen to plasmin <ref>Lin, H., Xu, L., Yu, S., Hong, W., Huang, M., & Xu, P. (2020). Therapeutics targeting the fibrinolytic system. Experimental & molecular medicine, 52(3), 367-379. PMID: 32152451 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156416/ PMC7156416] DOI: 10.1038/s12276-020-0397-x</ref>) and tPA (Tissue plasminogen activator, a fibrin-dependent enzyme primarily involved in dissolving blood clots<ref>Rakic, J. M., Maillard, C., Jost, M., Bajou, K., Masson, V., Devy, L., ... & Noël, A. (2003). Role of plasminogen activator-plasmin system in tumor angiogenesis. Cellular and Molecular Life Sciences CMLS, 60, 463-473. PMID: 12737307 [https://doi.org/10.1007/s000180300039 DOI: 10.1007/s000180300039]</ref>), thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively.<ref>Ismail, A. A., Shaker, B. T., & Bajou, K. (2021). The plasminogen–activator plasmin system in physiological and pathophysiological angiogenesis. International Journal of Molecular Sciences, 23(1), 337. PMID: 35008762 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745544/ PMC8745544] DOI: 10.3390/ijms23010337</ref>
			Persistent heart damage disrupts the balance between fibrotic repair and its negative feedback regulation, leading to over-activation of myofibroblasts and excessive accumulation of ECM.<ref>Thomas, T. P., & Grisanti, L. A. (2020). The dynamic interplay between cardiac inflammation and fibrosis. Frontiers in physiology, 11, 529075. PMID: 33041853 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522448/ PMC7522448] DOI: 10.3389/fphys.2020.529075</ref>

	Plasma PAI-1 levels are known to oscillate in a circadian rhythm, peaking in the morning thereby reducing fibrinolytic potential. This diurnal variation in PAI-1 has been postulated to '''explain the morning peak in adverse cardiovascular events'''.<ref>Yu, Y., Li, W., Xu, L., & Wang, Y. (2023). Circadian rhythm of plasminogen activator inhibitor-1 and cardiovascular complications in type 2 diabetes. Frontiers in Endocrinology, 14, 1124353. PMID: 37020596 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067678/ PMC10067678] DOI: 10.3389/fendo.2023.1124353</ref>		Plasma PAI-1 levels are known to oscillate in a circadian rhythm, peaking in the morning thereby reducing fibrinolytic potential. This diurnal variation in PAI-1 has been postulated to '''explain the morning peak in adverse cardiovascular events'''.<ref>Yu, Y., Li, W., Xu, L., & Wang, Y. (2023). Circadian rhythm of plasminogen activator inhibitor-1 and cardiovascular complications in type 2 diabetes. Frontiers in Endocrinology, 14, 1124353. PMID: 37020596 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067678/ PMC10067678] DOI: 10.3389/fendo.2023.1124353</ref>

	After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>		After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref> Paradoxically, lack of PAI-1 in the heart is associated with the development of cardiac fibrosis in aged mice. Zymographic analysis revealed that matrix metalloproteinase-2 enzymatic activity was elevated in PAI-1-deficient mouse cardiac endothelial cells.<ref>Ghosh, A. K., Bradham, W. S., Gleaves, L. A., De Taeye, B., Murphy, S. B., Covington, J. W., & Vaughan, D. E. (2010). Genetic deficiency of plasminogen activator inhibitor-1 promotes cardiac fibrosis in aged mice: involvement of constitutive transforming growth factor-β signaling and endothelial-to-mesenchymal transition. Circulation, 122(12), 1200-1209. PMID: 20823384 DOI: 10.1161/CIRCULATIONAHA.110.955245</ref> Significantly enhanced multiple TGF-β signaling elements and transcriptional targets, explains the paradoxical effect of PAI-1 deficiency in promoting cardiac-selective fibrosis. Thus, PAI-1 is a molecular switch that controls the cardiac TGF-β axis and its early transcriptional effects that lead to myocardial fibrosis.<ref>Flevaris, P., Khan, S. S., Eren, M., Schuldt, A. J., Shah, S. J., Lee, D. C., ... & Vaughan, D. E. (2017). Plasminogen activator inhibitor type I controls cardiomyocyte transforming growth factor-β and cardiac fibrosis. Circulation, 136(7), 664-679. PMID: 28588076 PMC5784400 DOI: 10.1161/CIRCULATIONAHA.117.028145</ref>

			== PAI-1 role in hepatic lipoprotein regulation ==
			Upon lipid loading of hepatocytes, PAI-1 forms a complex with tPA and sequesters tPA away from apoB, which allows apoB to be lipidated and facilitates very-low-density lipoprotein (VLDL) assembly and secretion. Consistent with these findings, humans with PAI-1 deficiency have smaller VLDL particles and lower plasma levels of atherogenic apoB-lipoprotein cholesterol and cardiovascular risk.<ref>Dai, W., Zhang, H., Lund, H., Zhang, Z., Castleberry, M., Rodriguez, M., ... & Zheng, Z. (2023). Intracellular tPA–PAI-1 interaction determines VLDL assembly in hepatocytes. Science, 381(6661), eadh5207. PMID: 37651538 PMC10697821 (available on 2024-09-01) DOI: 10.1126/science.adh5207</ref>

	== DNA-methylation based regulation of PAI-1 gene transcription ==		== DNA-methylation based regulation of PAI-1 gene transcription ==

Dmitry Dzhagarov at 13:59, 12 December 2023

2023-12-12T13:59:03Z

← Older revision		Revision as of 13:59, 12 December 2023
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	'''PAI-1 (Plasminogen activator inhibitor-1)''', also known as endothelial plasminogen activator inhibitor ('''serpin E1''') is a 45 kDa glycoprotein that in humans is encoded by the SERPINE1 gene (also named PLANH1), located on chromosome 7 (7q21.3-q22).<ref>Klinger, K. W., Wingqvist, R., Andreasen, P. A., Stuart, N., Stanislovitis, P., Watkins, P., ... & Dano, K. (1987). [https://europepmc.org/article/MED/2891140 Plasminogen activator inhibitor type 1 gene is located at region q21.3-q22 of chromosome 7 and genetically linked with cystic fibrosis]. Proceedings of the National Academy of Sciences of the United States of America. 84(23) 8548-8552 https://doi.org/10.1073/pnas.84.23.854</ref><ref>[https://www.ncbi.nlm.nih.gov/gene/5054 SERPINE1 serpin family E member 1 [ Homo sapiens (human), Gene ID: 5054]</ref>		'''PAI-1 (Plasminogen activator inhibitor-1)''', also known as endothelial plasminogen activator inhibitor ('''serpin E1''') is a 45 kDa glycoprotein that in humans is encoded by the SERPINE1 gene (also named PLANH1), located on chromosome 7 (7q21.3-q22).<ref>Klinger, K. W., Wingqvist, R., Andreasen, P. A., Stuart, N., Stanislovitis, P., Watkins, P., ... & Dano, K. (1987). [https://europepmc.org/article/MED/2891140 Plasminogen activator inhibitor type 1 gene is located at region q21.3-q22 of chromosome 7 and genetically linked with cystic fibrosis]. Proceedings of the National Academy of Sciences of the United States of America. 84(23) 8548-8552 https://doi.org/10.1073/pnas.84.23.854</ref><ref>[https://www.ncbi.nlm.nih.gov/gene/5054 SERPINE1 serpin family E member 1 [ Homo sapiens (human), Gene ID: 5054]</ref>

			== PAI-1 as a direct mediator of cellular senescence ==
	PAI-1 is a key component of the [[Cellular senescence#SASP\|SASP]] and a direct mediator of cellular senescence.<ref>Rana, T., Jiang, C., Liu, G., Miyata, T., Antony, V., Thannickal, V. J., & Liu, R. M. (2020). PAI-1 regulation of TGF-β1–induced alveolar type II cell senescence, SASP secretion, and SASP-mediated activation of alveolar macrophages. American journal of respiratory cell and molecular biology, 62(3), 319-330. PMID: 31513752 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055702/ PMC7055702] DOI: 10.1165/rcmb.2019-0071OC</ref><ref>Vaughan, D. E., Rai, R., Khan, S. S., Eren, M., & Ghosh, A. K. (2017). Plasminogen activator inhibitor-1 is a marker and a mediator of senescence. Arteriosclerosis, thrombosis, and vascular biology, 37(8), 1446-1452. PMID: 28572158 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846199/ PMC5846199] DOI: 10.1161/ATVBAHA.117.309451</ref><ref>Eren, M., Boe, A. E., Murphy, S. B., Place, A. T., Nagpal, V., Morales-Nebreda, L., ... & Vaughan, D. E. (2014). PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proceedings of the National Academy of Sciences, 111(19), 7090-7095. PMID: 24778222 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024885/ PMC4024885] DOI: 10.1073/pnas.1321942111</ref><ref>Sun, T., Ghosh, A. K., Eren, M., Miyata, T., & Vaughan, D. E. (2019). PAI-1 contributes to homocysteine-induced cellular senescence. Cellular signalling, 64, 109394. PMID: 31472244 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936332/ PMC6936332] DOI: 10.1016/j.cellsig.2019.109394</ref> Several studies have shown that PAI-1 induces cell senescence by activating the [[P53 protein involvement in Longevity\|p53–p21 signaling pathway]] and inhibiting the degradation of p53.<ref>Rana, T., Jiang, C., Banerjee, S., Yi, N., Zmijewski, J. W., Liu, G., & Liu, R. M. (2023). PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells. Cells, 12(15), 2008. PMID: 37566086 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417428/ PMC10417428] DOI: 10.3390/cells12152008</ref> The mechanism of PAI-1 transcription in senescent cells appears to be dependent on signaling of caveolin-1 (the principle component of cholesterol and sphingolipids-rich caveolar domains<ref>Prakash, S., Krishna, A., & Sengupta, D. (2021). Caveolin induced membrane curvature and lipid clustering: two sides of the same coin?. Faraday Discussions, 232, 218-235. PMID: 34545870 DOI: 10.1039/d0fd00062k</ref>). The master regulator of aging-associated tissue fibrosis factor TGF-β1 failed to induce PAI-1 expression in caveolin-1-null cells and restoration of caveolin-1 in caveolin-1-deficient cells rescues TGF-β1 inducibility of the PAI-1 gene.<ref>Samarakoon, R., Higgins, S. P., Higgins, C. E., & Higgins, P. J. (2019). The TGF-β1/p53/PAI-1 signaling axis in vascular senescence: Role of caveolin-1. Biomolecules, 9(8), 341. PMID: 31382626 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723262/ PMC6723262] DOI: 10.3390/biom9080341</ref>		PAI-1 is a key component of the [[Cellular senescence#SASP\|SASP]] and a direct mediator of cellular senescence.<ref>Rana, T., Jiang, C., Liu, G., Miyata, T., Antony, V., Thannickal, V. J., & Liu, R. M. (2020). PAI-1 regulation of TGF-β1–induced alveolar type II cell senescence, SASP secretion, and SASP-mediated activation of alveolar macrophages. American journal of respiratory cell and molecular biology, 62(3), 319-330. PMID: 31513752 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055702/ PMC7055702] DOI: 10.1165/rcmb.2019-0071OC</ref><ref>Vaughan, D. E., Rai, R., Khan, S. S., Eren, M., & Ghosh, A. K. (2017). Plasminogen activator inhibitor-1 is a marker and a mediator of senescence. Arteriosclerosis, thrombosis, and vascular biology, 37(8), 1446-1452. PMID: 28572158 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846199/ PMC5846199] DOI: 10.1161/ATVBAHA.117.309451</ref><ref>Eren, M., Boe, A. E., Murphy, S. B., Place, A. T., Nagpal, V., Morales-Nebreda, L., ... & Vaughan, D. E. (2014). PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proceedings of the National Academy of Sciences, 111(19), 7090-7095. PMID: 24778222 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024885/ PMC4024885] DOI: 10.1073/pnas.1321942111</ref><ref>Sun, T., Ghosh, A. K., Eren, M., Miyata, T., & Vaughan, D. E. (2019). PAI-1 contributes to homocysteine-induced cellular senescence. Cellular signalling, 64, 109394. PMID: 31472244 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936332/ PMC6936332] DOI: 10.1016/j.cellsig.2019.109394</ref> Several studies have shown that PAI-1 induces cell senescence by activating the [[P53 protein involvement in Longevity\|p53–p21 signaling pathway]] and inhibiting the degradation of p53.<ref>Rana, T., Jiang, C., Banerjee, S., Yi, N., Zmijewski, J. W., Liu, G., & Liu, R. M. (2023). PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells. Cells, 12(15), 2008. PMID: 37566086 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417428/ PMC10417428] DOI: 10.3390/cells12152008</ref> The mechanism of PAI-1 transcription in senescent cells appears to be dependent on signaling of caveolin-1 (the principle component of cholesterol and sphingolipids-rich caveolar domains<ref>Prakash, S., Krishna, A., & Sengupta, D. (2021). Caveolin induced membrane curvature and lipid clustering: two sides of the same coin?. Faraday Discussions, 232, 218-235. PMID: 34545870 DOI: 10.1039/d0fd00062k</ref>). The master regulator of aging-associated tissue fibrosis factor TGF-β1 failed to induce PAI-1 expression in caveolin-1-null cells and restoration of caveolin-1 in caveolin-1-deficient cells rescues TGF-β1 inducibility of the PAI-1 gene.<ref>Samarakoon, R., Higgins, S. P., Higgins, C. E., & Higgins, P. J. (2019). The TGF-β1/p53/PAI-1 signaling axis in vascular senescence: Role of caveolin-1. Biomolecules, 9(8), 341. PMID: 31382626 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723262/ PMC6723262] DOI: 10.3390/biom9080341</ref>

			== PAI-1 and age-related tissue fibrosis ==
			Fibrosis in numerous diseases including systemic sclerosis, pulmonary hypertension, renal hypertension, cardiac hypertension, myocardial infarction (MI), alcoholic liver disease and nonalcoholic steatohepatitis (NASH) may share common mechanisms. Tissue injury causes damage of blood vessels and the extravasation of plasma proteins, including fibrinogen, which results in the formation of a fibrin clot in the surrounding interstitium. This extracellular matrix of extravasated fibrin serves as a provisional matrix, into which cells can infiltrate during the subsequent wound healing. During the formation of a granulation tissue the cells disrupt existing cell-matrix interactions and locally degrade the surrounding [[extracellular matrix]] (ECM); they migrate, proliferate, and form new capillarylike tubular structures, which become stabilized by collagen synthesis in the course of time.<ref>Barrasa-Ramos, S., Dessalles, C. A., Hautefeuille, M., & Barakat, A. I. (2022). Mechanical regulation of the early stages of angiogenesis. Journal of the Royal Society Interface, 19(197), 20220360. PMID: 36475392 PMCID: PMC9727679 DOI: 10.1098/rsif.2022.0360</ref> The temporary fibrin matrix can be degraded by plasmin, which is activated from its zymogen plasminogen by 2 types of plasminogen activators, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA).<ref>Booth, N. A. (1999). Fibrinolysis and thrombosis. Best Practice & Research Clinical Haematology, 12(3), 423-433. PMID: 10856979 DOI: 10.1053/beha.1999.0034</ref> In addition to the u-PA/plasmin system, matrix metalloproteinases (MMPs) are also involved in the degradation of the extracellular matrix.<ref>Cabral-Pacheco, G. A., Garza-Veloz, I., Castruita-De la Rosa, C., Ramirez-Acuna, J. M., Perez-Romero, B. A., Guerrero-Rodriguez, J. F., ... & Martinez-Fierro, M. L. (2020). The roles of matrix metalloproteinases and their inhibitors in human diseases. International journal of molecular sciences, 21(24), 9739. https://doi.org/10.3390/ijms21249739</ref><ref>de Almeida, L. G., Thode, H., Eslambolchi, Y., Chopra, S., Young, D., Gill, S., ... & Dufour, A. (2022). Matrix metalloproteinases: From molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacological Reviews, 74(3), 714-770. PMID: 35738680 DOI: 10.1124/pharmrev.121.000349</ref>

	Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.<ref>Urano, T., Suzuki, Y., Iwaki, T., Sano, H., Honkura, N., & Castellino, F. J. (2019). Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis. Current drug targets, 20(16), 1695-1701. PMID: 31309890 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696651/ PMC7696651] DOI: 10.2174/1389450120666190715102510</ref><ref>Sillen, M., & Declerck, P. J. (2021). A narrative review on plasminogen activator inhibitor-1 and its (patho) physiological role: to target or not to target?. International journal of molecular sciences, 22(5), 2721. PMID: 33800359 PMCID: PMC7962805 DOI: 10.3390/ijms22052721</ref> PAI-1 is the main inhibitor of uPA (urokinase-type plasminogen activator, fibrin-independent serine protease responsible for the activation of plasminongen to plasmin <ref>Lin, H., Xu, L., Yu, S., Hong, W., Huang, M., & Xu, P. (2020). Therapeutics targeting the fibrinolytic system. Experimental & molecular medicine, 52(3), 367-379. PMID: 32152451 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156416/ PMC7156416] DOI: 10.1038/s12276-020-0397-x</ref>) and tPA (Tissue plasminogen activator, a fibrin-dependent enzyme primarily involved in dissolving blood clots<ref>Rakic, J. M., Maillard, C., Jost, M., Bajou, K., Masson, V., Devy, L., ... & Noël, A. (2003). Role of plasminogen activator-plasmin system in tumor angiogenesis. Cellular and Molecular Life Sciences CMLS, 60, 463-473. PMID: 12737307 [https://doi.org/10.1007/s000180300039 DOI: 10.1007/s000180300039]</ref>), thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively.<ref>Ismail, A. A., Shaker, B. T., & Bajou, K. (2021). The plasminogen–activator plasmin system in physiological and pathophysiological angiogenesis. International Journal of Molecular Sciences, 23(1), 337. </ref>		Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.<ref>Ghosh, A. K., & Vaughan, D. E. (2012). PAI‐1 in tissue fibrosis. Journal of cellular physiology, 227(2), 493-507. PMID: 21465481 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204398/ PMC3204398] DOI: 10.1002/jcp.22783</ref><ref>Urano, T., Suzuki, Y., Iwaki, T., Sano, H., Honkura, N., & Castellino, F. J. (2019). Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis. Current drug targets, 20(16), 1695-1701. PMID: 31309890 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696651/ PMC7696651] DOI: 10.2174/1389450120666190715102510</ref><ref>Sillen, M., & Declerck, P. J. (2021). A narrative review on plasminogen activator inhibitor-1 and its (patho) physiological role: to target or not to target?. International journal of molecular sciences, 22(5), 2721. PMID: 33800359 PMCID: PMC7962805 DOI: 10.3390/ijms22052721</ref> PAI-1 is the main inhibitor of uPA (urokinase-type plasminogen activator, fibrin-independent serine protease responsible for the activation of plasminongen to plasmin <ref>Lin, H., Xu, L., Yu, S., Hong, W., Huang, M., & Xu, P. (2020). Therapeutics targeting the fibrinolytic system. Experimental & molecular medicine, 52(3), 367-379. PMID: 32152451 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156416/ PMC7156416] DOI: 10.1038/s12276-020-0397-x</ref>) and tPA (Tissue plasminogen activator, a fibrin-dependent enzyme primarily involved in dissolving blood clots<ref>Rakic, J. M., Maillard, C., Jost, M., Bajou, K., Masson, V., Devy, L., ... & Noël, A. (2003). Role of plasminogen activator-plasmin system in tumor angiogenesis. Cellular and Molecular Life Sciences CMLS, 60, 463-473. PMID: 12737307 [https://doi.org/10.1007/s000180300039 DOI: 10.1007/s000180300039]</ref>), thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively.<ref>Ismail, A. A., Shaker, B. T., & Bajou, K. (2021). The plasminogen–activator plasmin system in physiological and pathophysiological angiogenesis. International Journal of Molecular Sciences, 23(1), 337. PMID: 35008762 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745544/ PMC8745544] DOI: 10.3390/ijms23010337</ref>

	Plasma PAI-1 levels are known to oscillate in a circadian rhythm, peaking in the morning thereby reducing fibrinolytic potential. This diurnal variation in PAI-1 has been postulated to '''explain the morning peak in adverse cardiovascular events'''.<ref>Yu, Y., Li, W., Xu, L., & Wang, Y. (2023). Circadian rhythm of plasminogen activator inhibitor-1 and cardiovascular complications in type 2 diabetes. Frontiers in Endocrinology, 14, 1124353. PMID: 37020596 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067678/ PMC10067678] DOI: 10.3389/fendo.2023.1124353</ref>		Plasma PAI-1 levels are known to oscillate in a circadian rhythm, peaking in the morning thereby reducing fibrinolytic potential. This diurnal variation in PAI-1 has been postulated to '''explain the morning peak in adverse cardiovascular events'''.<ref>Yu, Y., Li, W., Xu, L., & Wang, Y. (2023). Circadian rhythm of plasminogen activator inhibitor-1 and cardiovascular complications in type 2 diabetes. Frontiers in Endocrinology, 14, 1124353. PMID: 37020596 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067678/ PMC10067678] DOI: 10.3389/fendo.2023.1124353</ref>
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	After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>		After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>

			== DNA-methylation based regulation of PAI-1 gene transcription ==
	Recently DNA methylation (DNAm) based estimates of [[Epigenetic clock\|epigenetic age]] has become a widely used indicator of [[biological age]], as it has been shown to be strongly associated with morbidity and mortality, especially cardiovascular disease (CVD).<ref name="GrimAge" >Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., ... & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (albany NY), 11(2), 303. PMID: 30669119 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366976/ PMC6366976] DOI: 10.18632/aging.101684</ref> Of these DNAm based estimates of protein biomarkers, plasminogen activator inhibitor 1 (PAI1) is most strongly associated with morbidity.<ref name="GrimAge" /> A higher records of DNAm PAI-1 was strongly associated with coronary heart disease, hypertension, type 2 diabetes, computed tomography based measurements of adiposity, and early age of menopause for women, while lower DNAm PAI-1 was associated with disease free status and better physical functioning.<ref name="GrimAge" /> At the same time a higher testosterone and a higher TE ratio (balance between testosterone and estradiol), among relatively old men were associated with a decreased epigenetic age acceleration or low DNAm PAI-1.<ref>Kusters, C. D., Paul, K. C., Lu, A. T., Ferrucci, L., Ritz, B. R., Binder, A. M., & Horvath, S. (2023). Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and '''DNA-methylation based PAI1'''. GeroScience, 1-17. PMID: 37369886 [https://doi.org/10.1007/s11357-023-00832-3 DOI: 10.1007/s11357-023-00832-3] also [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980235/ PMC9980235]</ref>		Recently DNA methylation (DNAm) based estimates of [[Epigenetic clock\|epigenetic age]] has become a widely used indicator of [[biological age]], as it has been shown to be strongly associated with morbidity and mortality, especially cardiovascular disease (CVD).<ref name="GrimAge" >Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., ... & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (albany NY), 11(2), 303. PMID: 30669119 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366976/ PMC6366976] DOI: 10.18632/aging.101684</ref> Of these DNAm based estimates of protein biomarkers, plasminogen activator inhibitor 1 (PAI1) is most strongly associated with morbidity.<ref name="GrimAge" /> A higher records of DNAm PAI-1 was strongly associated with coronary heart disease, hypertension, type 2 diabetes, computed tomography based measurements of adiposity, and early age of menopause for women, while lower DNAm PAI-1 was associated with disease free status and better physical functioning.<ref name="GrimAge" /> At the same time a higher testosterone and a higher TE ratio (balance between testosterone and estradiol), among relatively old men were associated with a decreased epigenetic age acceleration or low DNAm PAI-1.<ref>Kusters, C. D., Paul, K. C., Lu, A. T., Ferrucci, L., Ritz, B. R., Binder, A. M., & Horvath, S. (2023). Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and '''DNA-methylation based PAI1'''. GeroScience, 1-17. PMID: 37369886 [https://doi.org/10.1007/s11357-023-00832-3 DOI: 10.1007/s11357-023-00832-3] also [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980235/ PMC9980235]</ref>

Dmitry Dzhagarov at 17:38, 11 December 2023

2023-12-11T17:38:13Z

← Older revision		Revision as of 17:38, 11 December 2023
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	'''PAI-1 (Plasminogen activator inhibitor-1)''', also known as endothelial plasminogen activator inhibitor ('''serpin E1''') is a 45 kDa glycoprotein that in humans is encoded by the SERPINE1 gene (also named PLANH1), located on chromosome 7 (7q21.3-q22).<ref>Klinger, K. W., Wingqvist, R., Andreasen, P. A., Stuart, N., Stanislovitis, P., Watkins, P., ... & Dano, K. (1987). [https://europepmc.org/article/MED/2891140 Plasminogen activator inhibitor type 1 gene is located at region q21.3-q22 of chromosome 7 and genetically linked with cystic fibrosis]. Proceedings of the National Academy of Sciences of the United States of America. 84(23) 8548-8552 https://doi.org/10.1073/pnas.84.23.854</ref><ref>[https://www.ncbi.nlm.nih.gov/gene/5054 SERPINE1 serpin family E member 1 [ Homo sapiens (human), Gene ID: 5054]</ref>		'''PAI-1 (Plasminogen activator inhibitor-1)''', also known as endothelial plasminogen activator inhibitor ('''serpin E1''') is a 45 kDa glycoprotein that in humans is encoded by the SERPINE1 gene (also named PLANH1), located on chromosome 7 (7q21.3-q22).<ref>Klinger, K. W., Wingqvist, R., Andreasen, P. A., Stuart, N., Stanislovitis, P., Watkins, P., ... & Dano, K. (1987). [https://europepmc.org/article/MED/2891140 Plasminogen activator inhibitor type 1 gene is located at region q21.3-q22 of chromosome 7 and genetically linked with cystic fibrosis]. Proceedings of the National Academy of Sciences of the United States of America. 84(23) 8548-8552 https://doi.org/10.1073/pnas.84.23.854</ref><ref>[https://www.ncbi.nlm.nih.gov/gene/5054 SERPINE1 serpin family E member 1 [ Homo sapiens (human), Gene ID: 5054]</ref>

	PAI-1 is a key component of the [[Cellular senescence#SASP\|SASP]] and a direct mediator of cellular senescence.<ref>Rana, T., Jiang, C., Liu, G., Miyata, T., Antony, V., Thannickal, V. J., & Liu, R. M. (2020). PAI-1 regulation of TGF-β1–induced alveolar type II cell senescence, SASP secretion, and SASP-mediated activation of alveolar macrophages. American journal of respiratory cell and molecular biology, 62(3), 319-330. PMID: 31513752 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055702/ PMC7055702] DOI: 10.1165/rcmb.2019-0071OC</ref><ref>Vaughan, D. E., Rai, R., Khan, S. S., Eren, M., & Ghosh, A. K. (2017). Plasminogen activator inhibitor-1 is a marker and a mediator of senescence. Arteriosclerosis, thrombosis, and vascular biology, 37(8), 1446-1452. PMID: 28572158 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846199/ PMC5846199] DOI: 10.1161/ATVBAHA.117.309451</ref><ref>Eren, M., Boe, A. E., Murphy, S. B., Place, A. T., Nagpal, V., Morales-Nebreda, L., ... & Vaughan, D. E. (2014). PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proceedings of the National Academy of Sciences, 111(19), 7090-7095. PMID: 24778222 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024885/ PMC4024885] DOI: 10.1073/pnas.1321942111</ref><ref>Sun, T., Ghosh, A. K., Eren, M., Miyata, T., & Vaughan, D. E. (2019). PAI-1 contributes to homocysteine-induced cellular senescence. Cellular signalling, 64, 109394. PMID: 31472244 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936332/ PMC6936332] DOI: 10.1016/j.cellsig.2019.109394</ref> Several studies have shown that PAI-1 induces cell senescence by activating the [[P53 protein involvement in Longevity\|p53–p21 signaling pathway]] and inhibiting the degradation of p53.<ref>Rana, T., Jiang, C., Banerjee, S., Yi, N., Zmijewski, J. W., Liu, G., & Liu, R. M. (2023). PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells. Cells, 12(15), 2008. PMID: 37566086 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417428/ PMC10417428] DOI: 10.3390/cells12152008</ref> The mechanism of PAI-1 transcription in senescent cells appears to be dependent on signaling of caveolin-1 (the principle component of cholesterol and sphingolipids-rich caveolar domains<ref>Prakash, S., Krishna, A., & Sengupta, D. (2021). Caveolin induced membrane curvature and lipid clustering: two sides of the same coin?. Faraday Discussions, 232, 218-235. PMID: 34545870 DOI: 10.1039/d0fd00062k</ref>). The master regulator of aging-associated tissue fibrosis factor TGF-β1 failed to induce PAI-1 expression in caveolin-1-null cells and restoration of caveolin-1 in caveolin-1-deficient cells rescues TGF-β1 inducibility of the PAI-1 gene.<ref>Samarakoon, R., Higgins, S. P., Higgins, C. E., & Higgins, P. J. (2019). The TGF-β1/p53/PAI-1 signaling axis in vascular senescence: Role of caveolin-1. Biomolecules, 9(8), 341. PMID: 31382626 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723262/ PMC6723262 DOI: 10.3390/biom9080341</ref>		PAI-1 is a key component of the [[Cellular senescence#SASP\|SASP]] and a direct mediator of cellular senescence.<ref>Rana, T., Jiang, C., Liu, G., Miyata, T., Antony, V., Thannickal, V. J., & Liu, R. M. (2020). PAI-1 regulation of TGF-β1–induced alveolar type II cell senescence, SASP secretion, and SASP-mediated activation of alveolar macrophages. American journal of respiratory cell and molecular biology, 62(3), 319-330. PMID: 31513752 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055702/ PMC7055702] DOI: 10.1165/rcmb.2019-0071OC</ref><ref>Vaughan, D. E., Rai, R., Khan, S. S., Eren, M., & Ghosh, A. K. (2017). Plasminogen activator inhibitor-1 is a marker and a mediator of senescence. Arteriosclerosis, thrombosis, and vascular biology, 37(8), 1446-1452. PMID: 28572158 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846199/ PMC5846199] DOI: 10.1161/ATVBAHA.117.309451</ref><ref>Eren, M., Boe, A. E., Murphy, S. B., Place, A. T., Nagpal, V., Morales-Nebreda, L., ... & Vaughan, D. E. (2014). PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proceedings of the National Academy of Sciences, 111(19), 7090-7095. PMID: 24778222 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024885/ PMC4024885] DOI: 10.1073/pnas.1321942111</ref><ref>Sun, T., Ghosh, A. K., Eren, M., Miyata, T., & Vaughan, D. E. (2019). PAI-1 contributes to homocysteine-induced cellular senescence. Cellular signalling, 64, 109394. PMID: 31472244 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936332/ PMC6936332] DOI: 10.1016/j.cellsig.2019.109394</ref> Several studies have shown that PAI-1 induces cell senescence by activating the [[P53 protein involvement in Longevity\|p53–p21 signaling pathway]] and inhibiting the degradation of p53.<ref>Rana, T., Jiang, C., Banerjee, S., Yi, N., Zmijewski, J. W., Liu, G., & Liu, R. M. (2023). PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells. Cells, 12(15), 2008. PMID: 37566086 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417428/ PMC10417428] DOI: 10.3390/cells12152008</ref> The mechanism of PAI-1 transcription in senescent cells appears to be dependent on signaling of caveolin-1 (the principle component of cholesterol and sphingolipids-rich caveolar domains<ref>Prakash, S., Krishna, A., & Sengupta, D. (2021). Caveolin induced membrane curvature and lipid clustering: two sides of the same coin?. Faraday Discussions, 232, 218-235. PMID: 34545870 DOI: 10.1039/d0fd00062k</ref>). The master regulator of aging-associated tissue fibrosis factor TGF-β1 failed to induce PAI-1 expression in caveolin-1-null cells and restoration of caveolin-1 in caveolin-1-deficient cells rescues TGF-β1 inducibility of the PAI-1 gene.<ref>Samarakoon, R., Higgins, S. P., Higgins, C. E., & Higgins, P. J. (2019). The TGF-β1/p53/PAI-1 signaling axis in vascular senescence: Role of caveolin-1. Biomolecules, 9(8), 341. PMID: 31382626 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723262/ PMC6723262] DOI: 10.3390/biom9080341</ref>

	Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.<ref>Urano, T., Suzuki, Y., Iwaki, T., Sano, H., Honkura, N., & Castellino, F. J. (2019). Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis. Current drug targets, 20(16), 1695-1701. PMID: 31309890 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696651/ PMC7696651] DOI: 10.2174/1389450120666190715102510</ref><ref>Sillen, M., & Declerck, P. J. (2021). A narrative review on plasminogen activator inhibitor-1 and its (patho) physiological role: to target or not to target?. International journal of molecular sciences, 22(5), 2721. PMID: 33800359 PMCID: PMC7962805 DOI: 10.3390/ijms22052721</ref> PAI-1 is the main inhibitor of uPA (urokinase-type plasminogen activator, fibrin-independent serine protease responsible for the activation of plasminongen to plasmin <ref>Lin, H., Xu, L., Yu, S., Hong, W., Huang, M., & Xu, P. (2020). Therapeutics targeting the fibrinolytic system. Experimental & molecular medicine, 52(3), 367-379. PMID: 32152451 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156416/ PMC7156416] DOI: 10.1038/s12276-020-0397-x</ref>) and tPA (Tissue plasminogen activator, a fibrin-dependent enzyme primarily involved in dissolving blood clots<ref>Rakic, J. M., Maillard, C., Jost, M., Bajou, K., Masson, V., Devy, L., ... & Noël, A. (2003). Role of plasminogen activator-plasmin system in tumor angiogenesis. Cellular and Molecular Life Sciences CMLS, 60, 463-473. PMID: 12737307 [https://doi.org/10.1007/s000180300039 DOI: 10.1007/s000180300039]</ref>), thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively.<ref>Ismail, A. A., Shaker, B. T., & Bajou, K. (2021). The plasminogen–activator plasmin system in physiological and pathophysiological angiogenesis. International Journal of Molecular Sciences, 23(1), 337. </ref>		Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.<ref>Urano, T., Suzuki, Y., Iwaki, T., Sano, H., Honkura, N., & Castellino, F. J. (2019). Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis. Current drug targets, 20(16), 1695-1701. PMID: 31309890 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696651/ PMC7696651] DOI: 10.2174/1389450120666190715102510</ref><ref>Sillen, M., & Declerck, P. J. (2021). A narrative review on plasminogen activator inhibitor-1 and its (patho) physiological role: to target or not to target?. International journal of molecular sciences, 22(5), 2721. PMID: 33800359 PMCID: PMC7962805 DOI: 10.3390/ijms22052721</ref> PAI-1 is the main inhibitor of uPA (urokinase-type plasminogen activator, fibrin-independent serine protease responsible for the activation of plasminongen to plasmin <ref>Lin, H., Xu, L., Yu, S., Hong, W., Huang, M., & Xu, P. (2020). Therapeutics targeting the fibrinolytic system. Experimental & molecular medicine, 52(3), 367-379. PMID: 32152451 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156416/ PMC7156416] DOI: 10.1038/s12276-020-0397-x</ref>) and tPA (Tissue plasminogen activator, a fibrin-dependent enzyme primarily involved in dissolving blood clots<ref>Rakic, J. M., Maillard, C., Jost, M., Bajou, K., Masson, V., Devy, L., ... & Noël, A. (2003). Role of plasminogen activator-plasmin system in tumor angiogenesis. Cellular and Molecular Life Sciences CMLS, 60, 463-473. PMID: 12737307 [https://doi.org/10.1007/s000180300039 DOI: 10.1007/s000180300039]</ref>), thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively.<ref>Ismail, A. A., Shaker, B. T., & Bajou, K. (2021). The plasminogen–activator plasmin system in physiological and pathophysiological angiogenesis. International Journal of Molecular Sciences, 23(1), 337. </ref>

Dmitry Dzhagarov at 17:36, 11 December 2023

2023-12-11T17:36:01Z

← Older revision		Revision as of 17:36, 11 December 2023
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	After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>		After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>

	Recently DNA methylation (DNAm) based estimates of [[Epigenetic clock\|epigenetic age]] has become a widely used indicator of [[biological age]], as it has been shown to be strongly associated with morbidity and mortality, especially cardiovascular disease (CVD).<ref name="GrimAge" >Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., ... & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (albany NY), 11(2), 303. PMID: 30669119 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366976/ PMC6366976] DOI: 10.18632/aging.101684</ref> Of these DNAm based estimates of protein biomarkers, plasminogen activator inhibitor 1 (PAI1) is most strongly associated with morbidity.<ref name="GrimAge" /> A higher records of DNAm PAI-1 was strongly associated with coronary heart disease, hypertension, type 2 diabetes, computed tomography based measurements of adiposity, and early age of menopause for women, while lower DNAm PAI-1 was associated with disease free status and better physical functioning.<ref name="GrimAge" /> At the same time a higher testosterone and a higher TE ratio (balance between testosterone and estradiol), among relatively old men were associated with a decreased epigenetic age acceleration or low DNAm PAI-1.<ref>Kusters, C. D., Paul, K. C., Lu, A. T., Ferrucci, L., Ritz, B. R., Binder, A. M., & Horvath, S. (2023). Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and '''DNA-methylation based PAI1'''. GeroScience, 1-17. PMID: 37369886 [https://doi.org/10.1007/s11357-023-00832-3 DOI: 10.1007/s11357-023-00832-3] also [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980235/ PMC9980235]</ref>		Recently DNA methylation (DNAm) based estimates of [[Epigenetic clock\|epigenetic age]] has become a widely used indicator of [[biological age]], as it has been shown to be strongly associated with morbidity and mortality, especially cardiovascular disease (CVD).<ref name="GrimAge" >Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., ... & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (albany NY), 11(2), 303. PMID: 30669119 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366976/ PMC6366976] DOI: 10.18632/aging.101684</ref> Of these DNAm based estimates of protein biomarkers, plasminogen activator inhibitor 1 (PAI1) is most strongly associated with morbidity.<ref name="GrimAge" /> A higher records of DNAm PAI-1 was strongly associated with coronary heart disease, hypertension, type 2 diabetes, computed tomography based measurements of adiposity, and early age of menopause for women, while lower DNAm PAI-1 was associated with disease free status and better physical functioning.<ref name="GrimAge" /> At the same time a higher testosterone and a higher TE ratio (balance between testosterone and estradiol), among relatively old men were associated with a decreased epigenetic age acceleration or low DNAm PAI-1.<ref>Kusters, C. D., Paul, K. C., Lu, A. T., Ferrucci, L., Ritz, B. R., Binder, A. M., & Horvath, S. (2023). Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and '''DNA-methylation based PAI1'''. GeroScience, 1-17. PMID: 37369886 [https://doi.org/10.1007/s11357-023-00832-3 DOI: 10.1007/s11357-023-00832-3] also [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980235/ PMC9980235]</ref>

			The transcriptomic analyses identified PAI‑1 coupled with MMP‑9 as biomarkers of nonalcoholic steatohepatitis and the primary drivers of liver disease‑induced fibrosis.<ref>Zhao, Y., Yakufu, M., Ma, C., Wang, B., Yang, J., & Hu, J. (2024). Transcriptomics reveal a molecular signature in the progression of nonalcoholic steatohepatitis and identifies PAI‑1 and MMP‑9 as biomarkers in in vivo and in vitro studies. Molecular Medicine Reports, 29(1), 1-17. PMID: 38038126 [https://doi.org/10.3892/mmr.2023.13138 DOI: 10.3892/mmr.2023.13138]</ref>

	=== Natural substances have been shown to inhibit PAI-1 activity ===		=== Natural substances have been shown to inhibit PAI-1 activity ===

Dmitry Dzhagarov at 07:28, 11 December 2023

2023-12-11T07:28:41Z

← Older revision		Revision as of 07:28, 11 December 2023
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	After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>		After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>

	Recently DNA methylation (DNAm) based estimates of [[Epigenetic clock\|epigenetic age]] has become a widely used indicator of [[biological age]], as it has been shown to be strongly associated with morbidity and mortality, especially cardiovascular disease (CVD).<ref name="GrimAge" >Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., ... & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (albany NY), 11(2), 303. PMID: 30669119 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366976/ PMC6366976] DOI: 10.18632/aging.101684</ref> Of these DNAm based estimates of protein biomarkers, plasminogen activator inhibitor 1 (PAI1) is most strongly associated with morbidity.<ref name="GrimAge" /> A higher records of DNAm PAI-1 was strongly associated with coronary heart disease, hypertension, type 2 diabetes, computed tomography based measurements of adiposity, and early age of menopause for women, while lower DNAm PAI-1 was associated with disease free status and better physical functioning.<ref name="GrimAge" /> At the same time a higher testosterone and a higher TE ratio (balance between testosterone and estradiol), among relatively old men were associated with a decreased epigenetic age acceleration or low DNAm PAI-1.<ref>Kusters, C. D., Paul, K. C., Lu, A. T., Ferrucci, L., Ritz, B. R., Binder, A. M., & Horvath, S. (2023). Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and '''DNA-methylation based PAI1'''. GeroScience, 1-17. PMID: 37369886 [https://doi.org/10.1007/s11357-023-00832-3 DOI: 10.1007/s11357-023-00832-3]</ref>		Recently DNA methylation (DNAm) based estimates of [[Epigenetic clock\|epigenetic age]] has become a widely used indicator of [[biological age]], as it has been shown to be strongly associated with morbidity and mortality, especially cardiovascular disease (CVD).<ref name="GrimAge" >Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., ... & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (albany NY), 11(2), 303. PMID: 30669119 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366976/ PMC6366976] DOI: 10.18632/aging.101684</ref> Of these DNAm based estimates of protein biomarkers, plasminogen activator inhibitor 1 (PAI1) is most strongly associated with morbidity.<ref name="GrimAge" /> A higher records of DNAm PAI-1 was strongly associated with coronary heart disease, hypertension, type 2 diabetes, computed tomography based measurements of adiposity, and early age of menopause for women, while lower DNAm PAI-1 was associated with disease free status and better physical functioning.<ref name="GrimAge" /> At the same time a higher testosterone and a higher TE ratio (balance between testosterone and estradiol), among relatively old men were associated with a decreased epigenetic age acceleration or low DNAm PAI-1.<ref>Kusters, C. D., Paul, K. C., Lu, A. T., Ferrucci, L., Ritz, B. R., Binder, A. M., & Horvath, S. (2023). Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and '''DNA-methylation based PAI1'''. GeroScience, 1-17. PMID: 37369886 [https://doi.org/10.1007/s11357-023-00832-3 DOI: 10.1007/s11357-023-00832-3] also [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980235/ PMC9980235]</ref>

	=== Natural substances have been shown to inhibit PAI-1 activity ===		=== Natural substances have been shown to inhibit PAI-1 activity ===

Dmitry Dzhagarov at 07:16, 11 December 2023

2023-12-11T07:16:03Z

← Older revision		Revision as of 07:16, 11 December 2023
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	After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>		After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>

			Recently DNA methylation (DNAm) based estimates of [[Epigenetic clock\|epigenetic age]] has become a widely used indicator of [[biological age]], as it has been shown to be strongly associated with morbidity and mortality, especially cardiovascular disease (CVD).<ref name="GrimAge" >Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., ... & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (albany NY), 11(2), 303. PMID: 30669119 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366976/ PMC6366976] DOI: 10.18632/aging.101684</ref> Of these DNAm based estimates of protein biomarkers, plasminogen activator inhibitor 1 (PAI1) is most strongly associated with morbidity.<ref name="GrimAge" /> A higher records of DNAm PAI-1 was strongly associated with coronary heart disease, hypertension, type 2 diabetes, computed tomography based measurements of adiposity, and early age of menopause for women, while lower DNAm PAI-1 was associated with disease free status and better physical functioning.<ref name="GrimAge" /> At the same time a higher testosterone and a higher TE ratio (balance between testosterone and estradiol), among relatively old men were associated with a decreased epigenetic age acceleration or low DNAm PAI-1.<ref>Kusters, C. D., Paul, K. C., Lu, A. T., Ferrucci, L., Ritz, B. R., Binder, A. M., & Horvath, S. (2023). Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and '''DNA-methylation based PAI1'''. GeroScience, 1-17. PMID: 37369886 [https://doi.org/10.1007/s11357-023-00832-3 DOI: 10.1007/s11357-023-00832-3]</ref>

	=== Natural substances have been shown to inhibit PAI-1 activity ===		=== Natural substances have been shown to inhibit PAI-1 activity ===
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	Also see: Attenuation of the Synthesis of Plasminogen Activator Inhibitor Type 1 by Niacin.<ref>Brown, S. L., Sobel, B. E., & Fujii, S. (1995). Attenuation of the synthesis of plasminogen activator inhibitor type 1 by niacin: a potential link between lipid lowering and fibrinolysis. Circulation, 92(4), 767-772. PMID: 7641354 [https://doi.org/10.1161/01.CIR.92.4.767 DOI: 10.1161/01.cir.92.4.767]</ref>		Also see: Attenuation of the Synthesis of Plasminogen Activator Inhibitor Type 1 by Niacin.<ref>Brown, S. L., Sobel, B. E., & Fujii, S. (1995). Attenuation of the synthesis of plasminogen activator inhibitor type 1 by niacin: a potential link between lipid lowering and fibrinolysis. Circulation, 92(4), 767-772. PMID: 7641354 [https://doi.org/10.1161/01.CIR.92.4.767 DOI: 10.1161/01.cir.92.4.767]</ref>

	<ref>Kusters, C. D., Paul, K. C., Lu, A. T., Ferruci, L., Ritz, B. R., Binder, A. M., & Horvath, S. (2023). Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and '''DNA-methylation based PAI1'''. GeroScience, 1-17.</ref>

	=== Synthetic inhibitors of PAI-1 activity ===		=== Synthetic inhibitors of PAI-1 activity ===

Dmitry Dzhagarov at 05:31, 11 December 2023

2023-12-11T05:31:19Z

← Older revision		Revision as of 05:31, 11 December 2023
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	'''PAI-1 (Plasminogen activator inhibitor-1)''', also known as endothelial plasminogen activator inhibitor ('''serpin E1''') is a 45 kDa glycoprotein that in humans is encoded by the SERPINE1 gene (also named PLANH1), located on chromosome 7 (7q21.3-q22).<ref>Klinger, K. W., Wingqvist, R., Andreasen, P. A., Stuart, N., Stanislovitis, P., Watkins, P., ... & Dano, K. (1987). [https://europepmc.org/article/MED/2891140 Plasminogen activator inhibitor type 1 gene is located at region q21.3-q22 of chromosome 7 and genetically linked with cystic fibrosis]. Proceedings of the National Academy of Sciences of the United States of America. 84(23) 8548-8552 https://doi.org/10.1073/pnas.84.23.854</ref>		'''PAI-1 (Plasminogen activator inhibitor-1)''', also known as endothelial plasminogen activator inhibitor ('''serpin E1''') is a 45 kDa glycoprotein that in humans is encoded by the SERPINE1 gene (also named PLANH1), located on chromosome 7 (7q21.3-q22).<ref>Klinger, K. W., Wingqvist, R., Andreasen, P. A., Stuart, N., Stanislovitis, P., Watkins, P., ... & Dano, K. (1987). [https://europepmc.org/article/MED/2891140 Plasminogen activator inhibitor type 1 gene is located at region q21.3-q22 of chromosome 7 and genetically linked with cystic fibrosis]. Proceedings of the National Academy of Sciences of the United States of America. 84(23) 8548-8552 https://doi.org/10.1073/pnas.84.23.854</ref><ref>[https://www.ncbi.nlm.nih.gov/gene/5054 SERPINE1 serpin family E member 1 [ Homo sapiens (human), Gene ID: 5054]</ref>

	PAI-1 is a key component of the [[Cellular senescence#SASP\|SASP]] and a direct mediator of cellular senescence.<ref>Rana, T., Jiang, C., Liu, G., Miyata, T., Antony, V., Thannickal, V. J., & Liu, R. M. (2020). PAI-1 regulation of TGF-β1–induced alveolar type II cell senescence, SASP secretion, and SASP-mediated activation of alveolar macrophages. American journal of respiratory cell and molecular biology, 62(3), 319-330. PMID: 31513752 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055702/ PMC7055702] DOI: 10.1165/rcmb.2019-0071OC</ref><ref>Vaughan, D. E., Rai, R., Khan, S. S., Eren, M., & Ghosh, A. K. (2017). Plasminogen activator inhibitor-1 is a marker and a mediator of senescence. Arteriosclerosis, thrombosis, and vascular biology, 37(8), 1446-1452. PMID: 28572158 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846199/ PMC5846199] DOI: 10.1161/ATVBAHA.117.309451</ref><ref>Eren, M., Boe, A. E., Murphy, S. B., Place, A. T., Nagpal, V., Morales-Nebreda, L., ... & Vaughan, D. E. (2014). PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proceedings of the National Academy of Sciences, 111(19), 7090-7095. PMID: 24778222 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024885/ PMC4024885] DOI: 10.1073/pnas.1321942111</ref><ref>Sun, T., Ghosh, A. K., Eren, M., Miyata, T., & Vaughan, D. E. (2019). PAI-1 contributes to homocysteine-induced cellular senescence. Cellular signalling, 64, 109394. PMID: 31472244 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936332/ PMC6936332] DOI: 10.1016/j.cellsig.2019.109394</ref> Several studies have shown that PAI-1 induces cell senescence by activating the [[P53 protein involvement in Longevity\|p53–p21 signaling pathway]] and inhibiting the degradation of p53.<ref>Rana, T., Jiang, C., Banerjee, S., Yi, N., Zmijewski, J. W., Liu, G., & Liu, R. M. (2023). PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells. Cells, 12(15), 2008. PMID: 37566086 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417428/ PMC10417428] DOI: 10.3390/cells12152008</ref> The mechanism of PAI-1 transcription in senescent cells appears to be dependent on signaling of caveolin-1 (the principle component of cholesterol and sphingolipids-rich caveolar domains<ref>Prakash, S., Krishna, A., & Sengupta, D. (2021). Caveolin induced membrane curvature and lipid clustering: two sides of the same coin?. Faraday Discussions, 232, 218-235. PMID: 34545870 DOI: 10.1039/d0fd00062k</ref>). The master regulator of aging-associated tissue fibrosis factor TGF-β1 failed to induce PAI-1 expression in caveolin-1-null cells and restoration of caveolin-1 in caveolin-1-deficient cells rescues TGF-β1 inducibility of the PAI-1 gene.<ref>Samarakoon, R., Higgins, S. P., Higgins, C. E., & Higgins, P. J. (2019). The TGF-β1/p53/PAI-1 signaling axis in vascular senescence: Role of caveolin-1. Biomolecules, 9(8), 341. PMID: 31382626 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723262/ PMC6723262 DOI: 10.3390/biom9080341</ref>		PAI-1 is a key component of the [[Cellular senescence#SASP\|SASP]] and a direct mediator of cellular senescence.<ref>Rana, T., Jiang, C., Liu, G., Miyata, T., Antony, V., Thannickal, V. J., & Liu, R. M. (2020). PAI-1 regulation of TGF-β1–induced alveolar type II cell senescence, SASP secretion, and SASP-mediated activation of alveolar macrophages. American journal of respiratory cell and molecular biology, 62(3), 319-330. PMID: 31513752 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055702/ PMC7055702] DOI: 10.1165/rcmb.2019-0071OC</ref><ref>Vaughan, D. E., Rai, R., Khan, S. S., Eren, M., & Ghosh, A. K. (2017). Plasminogen activator inhibitor-1 is a marker and a mediator of senescence. Arteriosclerosis, thrombosis, and vascular biology, 37(8), 1446-1452. PMID: 28572158 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846199/ PMC5846199] DOI: 10.1161/ATVBAHA.117.309451</ref><ref>Eren, M., Boe, A. E., Murphy, S. B., Place, A. T., Nagpal, V., Morales-Nebreda, L., ... & Vaughan, D. E. (2014). PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proceedings of the National Academy of Sciences, 111(19), 7090-7095. PMID: 24778222 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024885/ PMC4024885] DOI: 10.1073/pnas.1321942111</ref><ref>Sun, T., Ghosh, A. K., Eren, M., Miyata, T., & Vaughan, D. E. (2019). PAI-1 contributes to homocysteine-induced cellular senescence. Cellular signalling, 64, 109394. PMID: 31472244 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936332/ PMC6936332] DOI: 10.1016/j.cellsig.2019.109394</ref> Several studies have shown that PAI-1 induces cell senescence by activating the [[P53 protein involvement in Longevity\|p53–p21 signaling pathway]] and inhibiting the degradation of p53.<ref>Rana, T., Jiang, C., Banerjee, S., Yi, N., Zmijewski, J. W., Liu, G., & Liu, R. M. (2023). PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells. Cells, 12(15), 2008. PMID: 37566086 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417428/ PMC10417428] DOI: 10.3390/cells12152008</ref> The mechanism of PAI-1 transcription in senescent cells appears to be dependent on signaling of caveolin-1 (the principle component of cholesterol and sphingolipids-rich caveolar domains<ref>Prakash, S., Krishna, A., & Sengupta, D. (2021). Caveolin induced membrane curvature and lipid clustering: two sides of the same coin?. Faraday Discussions, 232, 218-235. PMID: 34545870 DOI: 10.1039/d0fd00062k</ref>). The master regulator of aging-associated tissue fibrosis factor TGF-β1 failed to induce PAI-1 expression in caveolin-1-null cells and restoration of caveolin-1 in caveolin-1-deficient cells rescues TGF-β1 inducibility of the PAI-1 gene.<ref>Samarakoon, R., Higgins, S. P., Higgins, C. E., & Higgins, P. J. (2019). The TGF-β1/p53/PAI-1 signaling axis in vascular senescence: Role of caveolin-1. Biomolecules, 9(8), 341. PMID: 31382626 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723262/ PMC6723262 DOI: 10.3390/biom9080341</ref>

Dmitry Dzhagarov: /* Synthetic inhibitors of PAI-1 activity */

2023-12-10T16:44:46Z

Synthetic inhibitors of PAI-1 activity

← Older revision		Revision as of 16:44, 10 December 2023
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	Targeting PAI-1 may be an effective therapeutic strategy for the treatment of senescence-related diseases. The PAI-1 inhibitor '''TM5275''' attenuated TGFβ1-induced pulmonary fibrosis and alveolar type II cell senescence in mice.<ref>Huang, W. T., Vayalil, P. K., Miyata, T., Hagood, J., & Liu, R. M. (2012). Therapeutic value of small molecule inhibitor to plasminogen activator inhibitor–1 for lung fibrosis. American journal of respiratory cell and molecular biology, 46(1), 87-95. </ref><ref>Izuhara, Y., Yamaoka, N., Kodama, H., Dan, T., Takizawa, S., Hirayama, N., ... & Miyata, T. (2010). A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates. Journal of Cerebral Blood Flow & Metabolism, 30(5), 904-912. PMID: 20087372 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949193/ PMC2949193] DOI: 10.1038/jcbfm.2009.272</ref>		Targeting PAI-1 may be an effective therapeutic strategy for the treatment of senescence-related diseases. The PAI-1 inhibitor '''TM5275''' attenuated TGFβ1-induced pulmonary fibrosis and alveolar type II cell senescence in mice.<ref>Huang, W. T., Vayalil, P. K., Miyata, T., Hagood, J., & Liu, R. M. (2012). Therapeutic value of small molecule inhibitor to plasminogen activator inhibitor–1 for lung fibrosis. American journal of respiratory cell and molecular biology, 46(1), 87-95. </ref><ref>Izuhara, Y., Yamaoka, N., Kodama, H., Dan, T., Takizawa, S., Hirayama, N., ... & Miyata, T. (2010). A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates. Journal of Cerebral Blood Flow & Metabolism, 30(5), 904-912. PMID: 20087372 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949193/ PMC2949193] DOI: 10.1038/jcbfm.2009.272</ref>

			Pharmacological inhibition of PAI-1 with '''TM5614''' is a promising therapeutic approach to control cardiopulmonary and vascular pathologies including vascular thrombosis inflammatory and prothrombotic factors.<ref>Ghosh, A. K., Soberanes, S., Lux, E., Shang, M., Aillon, R. P., Eren, M., ... & Vaughan, D. E. (2021). Pharmacological inhibition of PAI-1 alleviates cardiopulmonary pathologies induced by exposure to air pollutants PM2. 5. Environmental Pollution, 287, 117283. PMID: 34426376 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434953/ PMC8434953] DOI: 10.1016/j.envpol.2021.117283</ref>

Dmitry Dzhagarov at 15:56, 10 December 2023

2023-12-10T15:56:24Z

← Older revision		Revision as of 15:56, 10 December 2023
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	'''PAI-1 (Plasminogen activator inhibitor-1)''', also known as endothelial plasminogen activator inhibitor ('''serpin E1''') is a ~~protein~~ that in humans is encoded by the SERPINE1 gene. PAI-1 is a key component of the SASP and a direct mediator of cellular senescence.<ref>Eren, M., Boe, A. E., Murphy, S. B., Place, A. T., Nagpal, V., Morales-Nebreda, L., ... & Vaughan, D. E. (2014). PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proceedings of the National Academy of Sciences, 111(19), 7090-7095. PMID: 24778222 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024885/ PMC4024885] DOI: 10.1073/pnas.1321942111</ref> Several studies have shown that PAI-1 induces cell senescence by activating the [[P53 protein involvement in Longevity\|p53–p21 signaling pathway]] and inhibiting the degradation of p53.<ref>Rana, T., Jiang, C., Banerjee, S., Yi, N., Zmijewski, J. W., Liu, G., & Liu, R. M. (2023). PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells. Cells, 12(15), 2008. PMID: 37566086 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417428/ PMC10417428] DOI: 10.3390/cells12152008</ref>		'''PAI-1 (Plasminogen activator inhibitor-1)''', also known as endothelial plasminogen activator inhibitor ('''serpin E1''') is a 45 kDa glycoprotein that in humans is encoded by the SERPINE1 gene (also named PLANH1), located on chromosome 7 (7q21.3-q22).<ref>Klinger, K. W., Wingqvist, R., Andreasen, P. A., Stuart, N., Stanislovitis, P., Watkins, P., ... & Dano, K. (1987). [https://europepmc.org/article/MED/2891140 Plasminogen activator inhibitor type 1 gene is located at region q21.3-q22 of chromosome 7 and genetically linked with cystic fibrosis]. Proceedings of the National Academy of Sciences of the United States of America. 84(23) 8548-8552 https://doi.org/10.1073/pnas.84.23.854</ref>

			PAI-1 is a key component of the [[Cellular senescence#SASP\|SASP]] and a direct mediator of cellular senescence.<ref>Rana, T., Jiang, C., Liu, G., Miyata, T., Antony, V., Thannickal, V. J., & Liu, R. M. (2020). PAI-1 regulation of TGF-β1–induced alveolar type II cell senescence, SASP secretion, and SASP-mediated activation of alveolar macrophages. American journal of respiratory cell and molecular biology, 62(3), 319-330. PMID: 31513752 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055702/ PMC7055702] DOI: 10.1165/rcmb.2019-0071OC</ref><ref>Vaughan, D. E., Rai, R., Khan, S. S., Eren, M., & Ghosh, A. K. (2017). Plasminogen activator inhibitor-1 is a marker and a mediator of senescence. Arteriosclerosis, thrombosis, and vascular biology, 37(8), 1446-1452. PMID: 28572158 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846199/ PMC5846199] DOI: 10.1161/ATVBAHA.117.309451</ref><ref>Eren, M., Boe, A. E., Murphy, S. B., Place, A. T., Nagpal, V., Morales-Nebreda, L., ... & Vaughan, D. E. (2014). PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proceedings of the National Academy of Sciences, 111(19), 7090-7095. PMID: 24778222 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024885/ PMC4024885] DOI: 10.1073/pnas.1321942111</ref><ref>Sun, T., Ghosh, A. K., Eren, M., Miyata, T., & Vaughan, D. E. (2019). PAI-1 contributes to homocysteine-induced cellular senescence. Cellular signalling, 64, 109394. PMID: 31472244 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936332/ PMC6936332] DOI: 10.1016/j.cellsig.2019.109394</ref> Several studies have shown that PAI-1 induces cell senescence by activating the [[P53 protein involvement in Longevity\|p53–p21 signaling pathway]] and inhibiting the degradation of p53.<ref>Rana, T., Jiang, C., Banerjee, S., Yi, N., Zmijewski, J. W., Liu, G., & Liu, R. M. (2023). PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells. Cells, 12(15), 2008. PMID: 37566086 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417428/ PMC10417428] DOI: 10.3390/cells12152008</ref> The mechanism of PAI-1 transcription in senescent cells appears to be dependent on signaling of caveolin-1 (the principle component of cholesterol and sphingolipids-rich caveolar domains<ref>Prakash, S., Krishna, A., & Sengupta, D. (2021). Caveolin induced membrane curvature and lipid clustering: two sides of the same coin?. Faraday Discussions, 232, 218-235. PMID: 34545870 DOI: 10.1039/d0fd00062k</ref>). The master regulator of aging-associated tissue fibrosis factor TGF-β1 failed to induce PAI-1 expression in caveolin-1-null cells and restoration of caveolin-1 in caveolin-1-deficient cells rescues TGF-β1 inducibility of the PAI-1 gene.<ref>Samarakoon, R., Higgins, S. P., Higgins, C. E., & Higgins, P. J. (2019). The TGF-β1/p53/PAI-1 signaling axis in vascular senescence: Role of caveolin-1. Biomolecules, 9(8), 341. PMID: 31382626 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723262/ PMC6723262 DOI: 10.3390/biom9080341</ref>

	Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.<ref>Urano, T., Suzuki, Y., Iwaki, T., Sano, H., Honkura, N., & Castellino, F. J. (2019). Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis. Current drug targets, 20(16), 1695-1701. PMID: 31309890 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696651/ PMC7696651] DOI: 10.2174/1389450120666190715102510</ref><ref>Sillen, M., & Declerck, P. J. (2021). A narrative review on plasminogen activator inhibitor-1 and its (patho) physiological role: to target or not to target?. International journal of molecular sciences, 22(5), 2721. PMID: 33800359 PMCID: PMC7962805 DOI: 10.3390/ijms22052721</ref> PAI-1 is the main inhibitor of uPA (urokinase-type plasminogen activator, fibrin-independent serine protease responsible for the activation of plasminongen to plasmin <ref>Lin, H., Xu, L., Yu, S., Hong, W., Huang, M., & Xu, P. (2020). Therapeutics targeting the fibrinolytic system. Experimental & molecular medicine, 52(3), 367-379. PMID: 32152451 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156416/ PMC7156416] DOI: 10.1038/s12276-020-0397-x</ref>) and tPA (Tissue plasminogen activator, a fibrin-dependent enzyme primarily involved in dissolving blood clots<ref>Rakic, J. M., Maillard, C., Jost, M., Bajou, K., Masson, V., Devy, L., ... & Noël, A. (2003). Role of plasminogen activator-plasmin system in tumor angiogenesis. Cellular and Molecular Life Sciences CMLS, 60, 463-473. PMID: 12737307 [https://doi.org/10.1007/s000180300039 DOI: 10.1007/s000180300039]</ref>), thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively.<ref>Ismail, A. A., Shaker, B. T., & Bajou, K. (2021). The plasminogen–activator plasmin system in physiological and pathophysiological angiogenesis. International Journal of Molecular Sciences, 23(1), 337. </ref>		Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.<ref>Urano, T., Suzuki, Y., Iwaki, T., Sano, H., Honkura, N., & Castellino, F. J. (2019). Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis. Current drug targets, 20(16), 1695-1701. PMID: 31309890 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696651/ PMC7696651] DOI: 10.2174/1389450120666190715102510</ref><ref>Sillen, M., & Declerck, P. J. (2021). A narrative review on plasminogen activator inhibitor-1 and its (patho) physiological role: to target or not to target?. International journal of molecular sciences, 22(5), 2721. PMID: 33800359 PMCID: PMC7962805 DOI: 10.3390/ijms22052721</ref> PAI-1 is the main inhibitor of uPA (urokinase-type plasminogen activator, fibrin-independent serine protease responsible for the activation of plasminongen to plasmin <ref>Lin, H., Xu, L., Yu, S., Hong, W., Huang, M., & Xu, P. (2020). Therapeutics targeting the fibrinolytic system. Experimental & molecular medicine, 52(3), 367-379. PMID: 32152451 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156416/ PMC7156416] DOI: 10.1038/s12276-020-0397-x</ref>) and tPA (Tissue plasminogen activator, a fibrin-dependent enzyme primarily involved in dissolving blood clots<ref>Rakic, J. M., Maillard, C., Jost, M., Bajou, K., Masson, V., Devy, L., ... & Noël, A. (2003). Role of plasminogen activator-plasmin system in tumor angiogenesis. Cellular and Molecular Life Sciences CMLS, 60, 463-473. PMID: 12737307 [https://doi.org/10.1007/s000180300039 DOI: 10.1007/s000180300039]</ref>), thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively.<ref>Ismail, A. A., Shaker, B. T., & Bajou, K. (2021). The plasminogen–activator plasmin system in physiological and pathophysiological angiogenesis. International Journal of Molecular Sciences, 23(1), 337. </ref>

			Plasma PAI-1 levels are known to oscillate in a circadian rhythm, peaking in the morning thereby reducing fibrinolytic potential. This diurnal variation in PAI-1 has been postulated to '''explain the morning peak in adverse cardiovascular events'''.<ref>Yu, Y., Li, W., Xu, L., & Wang, Y. (2023). Circadian rhythm of plasminogen activator inhibitor-1 and cardiovascular complications in type 2 diabetes. Frontiers in Endocrinology, 14, 1124353. PMID: 37020596 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067678/ PMC10067678] DOI: 10.3389/fendo.2023.1124353</ref>

	After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>		After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>

	=== Natural substances have been shown to inhibit PAI-1 activity ===		=== Natural substances have been shown to inhibit PAI-1 activity ===
	These include curcumin (from turmeric),<ref>Muneesa, M. F., Barki, R. R., Shaikh, S. B., & Bhandary, Y. P. (2022). Curcumin intervention during progressive fibrosis controls inflammatory cytokines and the fibrinolytic system in pulmonary fibrosis. Toxicology and Applied Pharmacology, 449, 116116. PMID: 35716765 DOI: 10.1016/j.taap.2022.116116</ref> epigallocatechin gallate (EGCG from green tea),<ref>Islam, M. S., Parish, M., Brennan, J. T., Winer, B. L., & Segars, J. H. (2023). Targeting fibrotic signaling pathways by EGCG as a therapeutic strategy for uterine fibroids. Scientific reports, 13(1), 8492. PMID: 37231028 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10212992/ PMC10212992] DOI: 10.1038/s41598-023-35212-6</ref> omega-3 fatty acids (from fish oil), and anthocyanins (from berries).		These include curcumin (from turmeric),<ref>Muneesa, M. F., Barki, R. R., Shaikh, S. B., & Bhandary, Y. P. (2022). Curcumin intervention during progressive fibrosis controls inflammatory cytokines and the fibrinolytic system in pulmonary fibrosis. Toxicology and Applied Pharmacology, 449, 116116. PMID: 35716765 DOI: 10.1016/j.taap.2022.116116</ref> epigallocatechin gallate (EGCG from green tea),<ref>Islam, M. S., Parish, M., Brennan, J. T., Winer, B. L., & Segars, J. H. (2023). Targeting fibrotic signaling pathways by EGCG as a therapeutic strategy for uterine fibroids. Scientific reports, 13(1), 8492. PMID: 37231028 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10212992/ PMC10212992] DOI: 10.1038/s41598-023-35212-6</ref> omega-3 fatty acids (from fish oil), baicalin,<ref>Lee, W., Ku, S. K., & Bae, J. S. (2015). Antiplatelet, anticoagulant, and profibrinolytic activities of baicalin. Archives of pharmacal research, 38, 893-903. PMID: 24849036 DOI: 10.1007/s12272-014-0410-9</ref><ref>Zhang, H. U., Liu, B., Jiang, S., Wu, J. F., Qi, C. H., Mohammadtursun, N., ... & Dong, J. C. (2021). Baicalin ameliorates cigarette smoke-induced airway inflammation in rats by modulating HDAC2/NF-κB/PAI-1 signalling. Pulmonary Pharmacology & Therapeutics, 70, 102061. PMID: 34314854 DOI: 10.1016/j.pupt.2021.102061</ref> and anthocyanins (from berries).

	Also see: Attenuation of the Synthesis of Plasminogen Activator Inhibitor Type 1 by Niacin.<ref>Brown, S. L., Sobel, B. E., & Fujii, S. (1995). Attenuation of the synthesis of plasminogen activator inhibitor type 1 by niacin: a potential link between lipid lowering and fibrinolysis. Circulation, 92(4), 767-772. PMID: 7641354 [https://doi.org/10.1161/01.CIR.92.4.767 DOI: 10.1161/01.cir.92.4.767]</ref>		Also see: Attenuation of the Synthesis of Plasminogen Activator Inhibitor Type 1 by Niacin.<ref>Brown, S. L., Sobel, B. E., & Fujii, S. (1995). Attenuation of the synthesis of plasminogen activator inhibitor type 1 by niacin: a potential link between lipid lowering and fibrinolysis. Circulation, 92(4), 767-772. PMID: 7641354 [https://doi.org/10.1161/01.CIR.92.4.767 DOI: 10.1161/01.cir.92.4.767]</ref>
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	=== Synthetic inhibitors of PAI-1 activity ===		=== Synthetic inhibitors of PAI-1 activity ===
			Targeting PAI-1 may be an effective therapeutic strategy for the treatment of senescence-related diseases. The PAI-1 inhibitor '''TM5275''' attenuated TGFβ1-induced pulmonary fibrosis and alveolar type II cell senescence in mice.<ref>Huang, W. T., Vayalil, P. K., Miyata, T., Hagood, J., & Liu, R. M. (2012). Therapeutic value of small molecule inhibitor to plasminogen activator inhibitor–1 for lung fibrosis. American journal of respiratory cell and molecular biology, 46(1), 87-95. </ref><ref>Izuhara, Y., Yamaoka, N., Kodama, H., Dan, T., Takizawa, S., Hirayama, N., ... & Miyata, T. (2010). A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates. Journal of Cerebral Blood Flow & Metabolism, 30(5), 904-912. PMID: 20087372 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949193/ PMC2949193] DOI: 10.1038/jcbfm.2009.272</ref>



	<ref>Qian, C., Ito, N., Tsuji, K., Sato, S., Kikuchi, K., Yoshii, T., ... & Asou, Y. (2023). A PAI‐1 antagonist ameliorates hypophosphatemia in the Hyp vitamin D‐resistant rickets model mouse. FEBS Open Bio.</ref><ref>Aobulikasimu, A., Liu, T., Piao, J., Sato, S., Ochi, H., Okawa, A., ... & Asou, Y. (2023). SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption. Scientific Reports, 13(1), 7991.</ref>		<ref>Qian, C., Ito, N., Tsuji, K., Sato, S., Kikuchi, K., Yoshii, T., ... & Asou, Y. (2023). A PAI‐1 antagonist ameliorates hypophosphatemia in the Hyp vitamin D‐resistant rickets model mouse. FEBS Open Bio.</ref><ref>Aobulikasimu, A., Liu, T., Piao, J., Sato, S., Ochi, H., Okawa, A., ... & Asou, Y. (2023). SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption. Scientific Reports, 13(1), 7991.</ref>

Dmitry Dzhagarov at 09:13, 10 December 2023

2023-12-10T09:13:23Z

← Older revision		Revision as of 09:13, 10 December 2023
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	'''PAI-1 (Plasminogen activator inhibitor-1)''', also known as endothelial plasminogen activator inhibitor ('''serpin E1''') is a protein that in humans is encoded by the SERPINE1 gene. PAI-1 is a key component of the SASP and a direct mediator of cellular senescence.<ref>Eren, M., Boe, A. E., Murphy, S. B., Place, A. T., Nagpal, V., Morales-Nebreda, L., ... & Vaughan, D. E. (2014). PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proceedings of the National Academy of Sciences, 111(19), 7090-7095. PMID: 24778222 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024885/ PMC4024885] DOI: 10.1073/pnas.1321942111</ref> Several studies have shown that PAI-1 induces cell senescence by activating the [[P53 protein involvement in Longevity\|p53–p21 signaling pathway]] and inhibiting the degradation of p53.<ref>Rana, T., Jiang, C., Banerjee, S., Yi, N., Zmijewski, J. W., Liu, G., & Liu, R. M. (2023). PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells. Cells, 12(15), 2008. PMID: 37566086 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417428/ PMC10417428] DOI: 10.3390/cells12152008</ref>		'''PAI-1 (Plasminogen activator inhibitor-1)''', also known as endothelial plasminogen activator inhibitor ('''serpin E1''') is a protein that in humans is encoded by the SERPINE1 gene. PAI-1 is a key component of the SASP and a direct mediator of cellular senescence.<ref>Eren, M., Boe, A. E., Murphy, S. B., Place, A. T., Nagpal, V., Morales-Nebreda, L., ... & Vaughan, D. E. (2014). PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proceedings of the National Academy of Sciences, 111(19), 7090-7095. PMID: 24778222 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024885/ PMC4024885] DOI: 10.1073/pnas.1321942111</ref> Several studies have shown that PAI-1 induces cell senescence by activating the [[P53 protein involvement in Longevity\|p53–p21 signaling pathway]] and inhibiting the degradation of p53.<ref>Rana, T., Jiang, C., Banerjee, S., Yi, N., Zmijewski, J. W., Liu, G., & Liu, R. M. (2023). PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells. Cells, 12(15), 2008. PMID: 37566086 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417428/ PMC10417428] DOI: 10.3390/cells12152008</ref>
	Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.<ref>Urano, T., Suzuki, Y., Iwaki, T., Sano, H., Honkura, N., & Castellino, F. J. (2019). Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis. Current drug targets, 20(16), 1695-1701. PMID: 31309890 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696651/ PMC7696651] DOI: 10.2174/1389450120666190715102510</ref><ref>Sillen, M., & Declerck, P. J. (2021). A narrative review on plasminogen activator inhibitor-1 and its (patho) physiological role: to target or not to target?. International journal of molecular sciences, 22(5), 2721. PMID: 33800359 PMCID: PMC7962805 DOI: 10.3390/ijms22052721</ref> PAI-1 is the main inhibitor of uPA (urokinase-type plasminogen activator, fibrin-independent serine protease responsible for the activation of plasminongen to plasmin <ref>Lin, H., Xu, L., Yu, S., Hong, W., Huang, M., & Xu, P. (2020). Therapeutics targeting the fibrinolytic system. Experimental & molecular medicine, 52(3), 367-379. PMID: 32152451 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156416/ PMC7156416] DOI: 10.1038/s12276-020-0397-x</ref>) and tPA (Tissue plasminogen activator, a fibrin-dependent enzyme primarily involved in dissolving blood clots<ref>Rakic, J. M., Maillard, C., Jost, M., Bajou, K., Masson, V., Devy, L., ... & Noël, A. (2003). Role of plasminogen activator-plasmin system in tumor angiogenesis. Cellular and Molecular Life Sciences CMLS, 60, 463-473. PMID: 12737307 [https://doi.org/10.1007/s000180300039 DOI: 10.1007/s000180300039]</ref>), thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively.<ref>Ismail, A. A., Shaker, B. T., & Bajou, K. (2021). The plasminogen–activator plasmin system in physiological and pathophysiological angiogenesis. International Journal of Molecular Sciences, 23(1), 337. </ref>		Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.<ref>Urano, T., Suzuki, Y., Iwaki, T., Sano, H., Honkura, N., & Castellino, F. J. (2019). Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis. Current drug targets, 20(16), 1695-1701. PMID: 31309890 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696651/ PMC7696651] DOI: 10.2174/1389450120666190715102510</ref><ref>Sillen, M., & Declerck, P. J. (2021). A narrative review on plasminogen activator inhibitor-1 and its (patho) physiological role: to target or not to target?. International journal of molecular sciences, 22(5), 2721. PMID: 33800359 PMCID: PMC7962805 DOI: 10.3390/ijms22052721</ref> PAI-1 is the main inhibitor of uPA (urokinase-type plasminogen activator, fibrin-independent serine protease responsible for the activation of plasminongen to plasmin <ref>Lin, H., Xu, L., Yu, S., Hong, W., Huang, M., & Xu, P. (2020). Therapeutics targeting the fibrinolytic system. Experimental & molecular medicine, 52(3), 367-379. PMID: 32152451 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156416/ PMC7156416] DOI: 10.1038/s12276-020-0397-x</ref>) and tPA (Tissue plasminogen activator, a fibrin-dependent enzyme primarily involved in dissolving blood clots<ref>Rakic, J. M., Maillard, C., Jost, M., Bajou, K., Masson, V., Devy, L., ... & Noël, A. (2003). Role of plasminogen activator-plasmin system in tumor angiogenesis. Cellular and Molecular Life Sciences CMLS, 60, 463-473. PMID: 12737307 [https://doi.org/10.1007/s000180300039 DOI: 10.1007/s000180300039]</ref>), thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively.<ref>Ismail, A. A., Shaker, B. T., & Bajou, K. (2021). The plasminogen–activator plasmin system in physiological and pathophysiological angiogenesis. International Journal of Molecular Sciences, 23(1), 337. </ref>

	After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>		After surveying the Amish community in the US state of Indiana, it was discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene.<ref>Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., ... & Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans. Science advances, 3(11), eaao1617. PMID: 29152572 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687852/ PMC5687852] DOI: 10.1126/sciadv.aao1617</ref>

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	Also see: Attenuation of the Synthesis of Plasminogen Activator Inhibitor Type 1 by Niacin.<ref>Brown, S. L., Sobel, B. E., & Fujii, S. (1995). Attenuation of the synthesis of plasminogen activator inhibitor type 1 by niacin: a potential link between lipid lowering and fibrinolysis. Circulation, 92(4), 767-772. PMID: 7641354 [https://doi.org/10.1161/01.CIR.92.4.767 DOI: 10.1161/01.cir.92.4.767]</ref>		Also see: Attenuation of the Synthesis of Plasminogen Activator Inhibitor Type 1 by Niacin.<ref>Brown, S. L., Sobel, B. E., & Fujii, S. (1995). Attenuation of the synthesis of plasminogen activator inhibitor type 1 by niacin: a potential link between lipid lowering and fibrinolysis. Circulation, 92(4), 767-772. PMID: 7641354 [https://doi.org/10.1161/01.CIR.92.4.767 DOI: 10.1161/01.cir.92.4.767]</ref>

			<ref>Kusters, C. D., Paul, K. C., Lu, A. T., Ferruci, L., Ritz, B. R., Binder, A. M., & Horvath, S. (2023). Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and '''DNA-methylation based PAI1'''. GeroScience, 1-17.</ref>

	=== Synthetic inhibitors of PAI-1 activity ===		=== Synthetic inhibitors of PAI-1 activity ===
			<ref>Qian, C., Ito, N., Tsuji, K., Sato, S., Kikuchi, K., Yoshii, T., ... & Asou, Y. (2023). A PAI‐1 antagonist ameliorates hypophosphatemia in the Hyp vitamin D‐resistant rickets model mouse. FEBS Open Bio.</ref><ref>Aobulikasimu, A., Liu, T., Piao, J., Sato, S., Ochi, H., Okawa, A., ... & Asou, Y. (2023). SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption. Scientific Reports, 13(1), 7991.</ref>

	== References ==		== References ==