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]



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