PAI-1 gene

From Longevity Wiki

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).[1][2]

PAI-1 as a direct mediator of cellular senescence

PAI-1 is a key component of the SASP and a direct mediator of cellular senescence.[3][4][5][6] Several studies have shown that PAI-1 induces cell senescence by activating the p53–p21 signaling pathway and inhibiting the degradation of p53.[7] 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[8]). 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.[9]

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.[10] 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).[11] In addition to the u-PA/plasmin system, matrix metalloproteinases (MMPs) are also involved in the degradation of the extracellular matrix.[12][13]

Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.[14][15][16] PAI-1 is the main inhibitor of uPA (urokinase-type plasminogen activator, fibrin-independent serine protease responsible for the activation of plasminongen to plasmin [17]) and tPA (Tissue plasminogen activator, a fibrin-dependent enzyme primarily involved in dissolving blood clots[18]), thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively.[19] 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.[20]

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.[21]

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.[22] 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.[23] 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.[24]

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.[25]

DNA-methylation based regulation of PAI-1 gene transcription

Recently DNA methylation (DNAm) based estimates of 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).[26] Of these DNAm based estimates of protein biomarkers, plasminogen activator inhibitor 1 (PAI1) is most strongly associated with morbidity.[26] 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.[26] 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.[27]

The transcriptomic analyses identified PAI‑1 coupled with MMP‑9 as biomarkers of nonalcoholic steatohepatitis and the primary drivers of liver disease‑induced fibrosis.[28]

Natural substances have been shown to inhibit PAI-1 activity

These include curcumin (from turmeric),[29] epigallocatechin gallate (EGCG from green tea),[30] omega-3 fatty acids (from fish oil), baicalin,[31][32] and anthocyanins (from berries).

Also see: Attenuation of the Synthesis of Plasminogen Activator Inhibitor Type 1 by Niacin.[33]


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.[34][35]

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.[36]


[37][38]

References

  1. ↑ Klinger, K. W., Wingqvist, R., Andreasen, P. A., Stuart, N., Stanislovitis, P., Watkins, P., ... & Dano, K. (1987). 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
  2. ↑ SERPINE1 serpin family E member 1 [ Homo sapiens (human), Gene ID: 5054
  3. ↑ 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 PMC7055702 DOI: 10.1165/rcmb.2019-0071OC
  4. ↑ 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 PMC5846199 DOI: 10.1161/ATVBAHA.117.309451
  5. ↑ 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 PMC4024885 DOI: 10.1073/pnas.1321942111
  6. ↑ 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 PMC6936332 DOI: 10.1016/j.cellsig.2019.109394
  7. ↑ 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 PMC10417428 DOI: 10.3390/cells12152008
  8. ↑ 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
  9. ↑ 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 PMC6723262 DOI: 10.3390/biom9080341
  10. ↑ 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
  11. ↑ Booth, N. A. (1999). Fibrinolysis and thrombosis. Best Practice & Research Clinical Haematology, 12(3), 423-433. PMID: 10856979 DOI: 10.1053/beha.1999.0034
  12. ↑ 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
  13. ↑ 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
  14. ↑ Ghosh, A. K., & Vaughan, D. E. (2012). PAI‐1 in tissue fibrosis. Journal of cellular physiology, 227(2), 493-507. PMID: 21465481 PMC3204398 DOI: 10.1002/jcp.22783
  15. ↑ 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 PMC7696651 DOI: 10.2174/1389450120666190715102510
  16. ↑ 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
  17. ↑ 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 PMC7156416 DOI: 10.1038/s12276-020-0397-x
  18. ↑ 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 DOI: 10.1007/s000180300039
  19. ↑ 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 PMC8745544 DOI: 10.3390/ijms23010337
  20. ↑ Thomas, T. P., & Grisanti, L. A. (2020). The dynamic interplay between cardiac inflammation and fibrosis. Frontiers in physiology, 11, 529075. PMID: 33041853 PMC7522448 DOI: 10.3389/fphys.2020.529075
  21. ↑ 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 PMC10067678 DOI: 10.3389/fendo.2023.1124353
  22. ↑ 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 PMC5687852 DOI: 10.1126/sciadv.aao1617
  23. ↑ 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
  24. ↑ 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
  25. ↑ 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
  26. ↑ 26.0 26.1 26.2 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 PMC6366976 DOI: 10.18632/aging.101684
  27. ↑ 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 DOI: 10.1007/s11357-023-00832-3 also PMC9980235
  28. ↑ 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 DOI: 10.3892/mmr.2023.13138
  29. ↑ 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
  30. ↑ 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 PMC10212992 DOI: 10.1038/s41598-023-35212-6
  31. ↑ 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
  32. ↑ 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
  33. ↑ 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 DOI: 10.1161/01.cir.92.4.767
  34. ↑ 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.
  35. ↑ 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 PMC2949193 DOI: 10.1038/jcbfm.2009.272
  36. ↑ 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 PMC8434953 DOI: 10.1016/j.envpol.2021.117283
  37. ↑ 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.
  38. ↑ 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.
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