Role of plasminogen activator inhibitor-1 (PAI-1) in age-related cardiovascular pathophysiology

Alireza Khoddam , Douglas Vaughan , Lisa Wilsbacher

The Journal of Cardiovascular Aging ›› 2025, Vol. 5 ›› Issue (2) : 8

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The Journal of Cardiovascular Aging ›› 2025, Vol. 5 ›› Issue (2) :8 DOI: 10.20517/jca.2024.38
Review Article

Role of plasminogen activator inhibitor-1 (PAI-1) in age-related cardiovascular pathophysiology

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Abstract

Cardiovascular aging underpins the development of age-related diseases, including heart failure and vascular dysfunction, and is driven by molecular and cellular mechanisms described in the hallmarks of aging. Plasminogen activator inhibitor-1 (PAI-1), a key regulator of fibrinolysis, also mediates processes like vascular stiffness, cellular senescence, and immune evasion. This review highlights PAI-1’s role in cardiovascular aging with a special emphasis on senescence, a key hallmark of aging. It further explores PAI-1’s therapeutic potential, with a focus on its contribution to ECM remodeling, senescence signaling, and immune checkpoint regulation. Targeting PAI-1 could provide a promising strategy to mitigate age-related cardiovascular disease.

Keywords

Cardiovascular disease / aging / senescence / vascular biology

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Alireza Khoddam, Douglas Vaughan, Lisa Wilsbacher. Role of plasminogen activator inhibitor-1 (PAI-1) in age-related cardiovascular pathophysiology. The Journal of Cardiovascular Aging, 2025, 5(2): 8 DOI:10.20517/jca.2024.38

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References

[1]

Cardiovascular diseases (CVDs). World Health Organization. 2021. Available from: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) [Last accessed on 22 Apr 2025].

[2]

Ageing and health. World Health Organization. 2024. Available from: https://www.who.int/news-room/fact-sheets/detail/ageing-and-health [Last accessed on 22 Apr 2025]

[3]

Austad SN.The geroscience hypothesis: is it possible to change the rate of aging? In: Sierra F, Kohanski R, editors. Advances in geroscience. Cham: Springer International Publishing; 2016. pp. 1-36.

[4]

López-Otín C,Partridge L,Kroemer G.Hallmarks of aging: an expanding universe.Cell2023;186:243-78

[5]

Abdellatif M,Sedej S.Hallmarks of cardiovascular ageing.Nat Rev Cardiol2023;20:754-77

[6]

Sillen M.Targeting PAI-1 in cardiovascular disease: structural insights into PAI-1 functionality and inhibition.Front Cardiovasc Med2020;7:622473 PMCID:PMC7782431

[7]

Loskutoff DJ,Erickson LA.Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells.Proc Natl Acad Sci USA1983;80:2956-60 PMCID:PMC393952

[8]

Eren M,Thomas PM,Miyata T.PAI-1 is a critical regulator of FGF23 homeostasis.Sci Adv2017;3:e1603259 PMCID:PMC5597312

[9]

Gerenu G,Ferrero H.Modulation of BDNF cleavage by plasminogen-activator inhibitor-1 contributes to Alzheimer's neuropathology and cognitive deficits.Biochim Biophys Acta Mol Basis Dis2017;1863:991-1001

[10]

Cai D,Duignan IJ.BDNF-mediated enhancement of inflammation and injury in the aging heart.Physiol Genomics2006;24:191-7

[11]

Elzi DJ,Song M,Weintraub ST.Plasminogen activator inhibitor 1-insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence.Proc Natl Acad Sci USA2012;109:12052-7 PMCID:PMC3409757

[12]

Wang H,Heuckeroth RO.PAI-1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA.FEBS Lett2007;581:3098-104

[13]

Morrow GB,Mutch NJ.A serpin with a finger in many PAIs: PAI-1’s central function in thromboinflammation and cardiovascular disease.Front Cardiovasc Med2021;8:653655 PMCID:PMC8085275

[14]

Tjärnlund-Wolf A,Lo EH.Plasminogen activator inhibitor-1 and thrombotic cerebrovascular diseases.Stroke2012;43:2833-9 PMCID:PMC3712849

[15]

Rizzo MR,Barbieri M.Elevated plasma activator inhibitor 1 is not related to insulin resistance and to gene polymorphism in healthy centenarians.Atherosclerosis2002;160:385-90

[16]

Samad F.Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice.Mol Med1996;2:568-82 PMCID:PMC2230189

[17]

Eren M,Atkinson JB,Vaughan DE.Age-dependent spontaneous coronary arterial thrombosis in transgenic mice that express a stable form of human plasminogen activator inhibitor-1.Circulation2002;106:491-6

[18]

Eren M,Atkinson JB,Declerck PJ.Reactive site-dependent phenotypic alterations in plasminogen activator inhibitor-1 transgenic mice.J Thromb Haemost2007;5:1500-8

[19]

Yamamoto K,Kojima T,Saito H.Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly.Cardiovasc Res2005;66:276-85

[20]

Laurent S,Asmar R.Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients.Hypertension2001;37:1236-41

[21]

Regnault V,Laurent S.Arterial stiffness: from basic primers to integrative physiology.Annu Rev Physiol2024;86:99-121

[22]

Lyle AN.Killing me unsoftly: causes and mechanisms of arterial stiffness.Arterioscler Thromb Vasc Biol2017;37:e1-11 PMCID:PMC5308873

[23]

Hickson SS,Graves M.The relationship of age with regional aortic stiffness and diameter.JACC Cardiovasc Imaging2010;3:1247-55

[24]

Kawasaki T,Yagi S,Hirai T.Non-invasive assessment of the age related changes in stiffness of major branches of the human arteries.Cardiovasc Res1987;21:678-87

[25]

Vatner SF,Vyzas C,Graham RM.Vascular stiffness in aging and disease.Front Physiol2021;12:762437 PMCID:PMC8688960

[26]

Chu CQ.Fibroblast Yap/Taz signaling in extracellular matrix homeostasis and tissue fibrosis.J Clin Med2024;13:3358 PMCID:PMC11204269

[27]

Ribeiro-Silva JC,Krieger JE.Dynamic crosstalk between vascular smooth muscle cells and the aged extracellular matrix.Int J Mol Sci2021;22:10175 PMCID:PMC8468233

[28]

Klingberg F,White ES.The myofibroblast matrix: implications for tissue repair and fibrosis.J Pathol2013;229:298-309 PMCID:PMC4005341

[29]

Kennelly PJ,McGuinness OP,Weil PA. Harper’s illustrated biochemistry, 32nd edition. 2023. Available from: https://archive.org/details/harpers-illustrated-biochemistry-thirty-second-edition-2023/mode/2up [Last accessed on 22 Apr 2025]

[30]

Kolpakov V,Kulik TJ.Nitric oxide-generating compounds inhibit total protein and collagen synthesis in cultured vascular smooth muscle cells.Circ Res1995;76:305-9

[31]

Diebold I,Bonello S.The ‘PAI-1 paradox’ in vascular remodelling.Thromb Haemost2008;100:984-91

[32]

Zaman AK,Schneider DJ.A profibrotic effect of plasminogen activator inhibitor type-1 (PAI-1) in the heart.Exp Biol Med2009;234:246-54

[33]

Lackie PM.Molecular portfolios: cells interacting with matrix in repairing airway epithelium: this editorial discusses the findings of the paper in this issue by Stevens et al. [3] pp. 1901-10.Clin Exp Allergy2008;38:1840-3

[34]

Gramley F,Plisiene J.Decreased plasminogen activator inhibitor and tissue metalloproteinase inhibitor expression may promote increased metalloproteinase activity with increasing duration of human atrial fibrillation.J Cardiovasc Electrophysiol2007;18:1076-82

[35]

Ghosh AK.PAI-1 in tissue fibrosis.J Cell Physiol2012;227:493-507 PMCID:PMC3204398

[36]

Kortlever RM,Bernards R.Transforming growth factor-beta requires its target plasminogen activator inhibitor-1 for cytostatic activity.J Biol Chem2008;283:24308-13 PMCID:PMC3259838

[37]

Pedroja BS,Imas AO,Bernstein AM.Plasminogen activator inhibitor-1 regulates integrin αvβ3 expression and autocrine transforming growth factor β signaling.J Biol Chem2009;284:20708-17 PMCID:PMC2742836

[38]

Boe AE,Murphy SB.Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-L-arginine methyl ester-induced hypertension and vascular senescence.Circulation2013;128:2318-24 PMCID:PMC3933362

[39]

Garcia V,Siragusa M.Unbiased proteomics identifies plasminogen activator inhibitor-1 as a negative regulator of endothelial nitric oxide synthase.Proc Natl Acad Sci USA2020;117:9497-507 PMCID:PMC7196906

[40]

Khoukaz HB,Schoenherr A.PAI-1 regulates the cytoskeleton and intrinsic stiffness of vascular smooth muscle cells.Arterioscler Thromb Vasc Biol2024;44:2191-203 PMCID:PMC11424258

[41]

Matsushita H,Glassford AJ,Chiu CP.eNOS activity is reduced in senescent human endothelial cells: preservation by hTERT immortalization.Circ Res2001;89:793-8

[42]

Campisi J.Cellular senescence: when bad things happen to good cells.Nat Rev Mol Cell Biol2007;8:729-40

[43]

Han Y.Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics.Exp Mol Med2023;55:1-12 PMCID:PMC9898542

[44]

Bloom SI,Lesniewski LA.Mechanisms and consequences of endothelial cell senescence.Nat Rev Cardiol2023;20:38-51 PMCID:PMC10026597

[45]

Stefens SJM,IJpma A.Increased vascular smooth muscle cell senescence in aneurysmal Fibulin-4 mutant mice.NPJ Aging2024;10:31 PMCID:PMC11189919

[46]

Gasek NS,Kirkland JL.Strategies for targeting senescent cells in human disease.Nat Aging2021;1:870-9 PMCID:PMC8612694

[47]

Burton DG,Ikeda K.Pathophysiology of vascular calcification: pivotal role of cellular senescence in vascular smooth muscle cells.Exp Gerontol2010;45:819-24

[48]

Baker DJ,Tchkonia T.Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.Nature2011;479:232-6 PMCID:PMC3468323

[49]

Baker DJ,Durik M.Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan.Nature2016;530:184-9

[50]

Zhang X,Carver CM.Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance.Nat Commun2022;13:5671 PMCID:PMC9515187

[51]

Zhu Y,Pirtskhalava T.The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.Aging Cell2015;14:644-58

[52]

Kirkland JL.Cellular senescence: a translational perspective.EBioMedicine2017;21:21-8 PMCID:PMC5514381

[53]

Tao W,Han JJ.Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators.Cell Metab2024;36:1126-43.e5

[54]

Vaughan DE,Khan SS,Ghosh AK.Plasminogen activator inhibitor-1 is a marker and a mediator of senescence.Arterioscler Thromb Vasc Biol2017;37:1446-52 PMCID:PMC5846199

[55]

Kortlever RM,Bernards R.Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence.Nat Cell Biol2006;8:877-84 PMCID:PMC2954492

[56]

Cesari M,Incalzi RA.Plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions.Cardiovasc Ther2010;28:e72-91 PMCID:PMC2958211

[57]

Eren M,Klyachko EA.Role of plasminogen activator inhibitor-1 in senescence and aging.Semin Thromb Hemost2014;40:645-51 PMCID:PMC6563930

[58]

Sillen M.A narrative review on plasminogen activator inhibitor-1 and its (patho)physiological role: to target or not to target?.Int J Mol Sci2021;22:2721 PMCID:PMC7962805

[59]

Sun T,Eren M,Vaughan DE.PAI-1 contributes to homocysteine-induced cellular senescence.Cell Signal2019;64:109394 PMCID:PMC6936332

[60]

Ghosh AK,Park KE.A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence.Oncotarget2016;7:72443-57 PMCID:PMC5341920

[61]

Uryga AK,Garrido AM.Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury.Commun Biol2021;4:611

[62]

Saggau C,Esser D.Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases.Immunity2024;57:2416-32.e8

[63]

Onorati A,Lin B.Upregulation of PD-L1 in senescence and aging.Mol Cell Biol2022;42:e0017122 PMCID:PMC9583718

[64]

Cho HJ,Yang EJ.Nintedanib induces senolytic effect via STAT3 inhibition.Cell Death Dis2022;13:760 PMCID:PMC9440251

[65]

Xu M,Ding H.Targeting senescent cells enhances adipogenesis and metabolic function in old age.Elife2015;4:e12997

[66]

Xu M,Ding H.JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age.Proc Natl Acad Sci USA2015;112:E6301-10 PMCID:PMC4655580

[67]

Wang TW,Suzuki N.Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes.Nature2022;611:358-64

[68]

Suero-Abreu GA,Neilan TG.Atherosclerosis with immune checkpoint inhibitor therapy: evidence, diagnosis, and management: JACC: CardioOncology state-of-the-art review.JACC CardioOncol2022;4:598-615 PMCID:PMC9830225

[69]

Ibrahim AA,Uno T.Plasminogen activator inhibitor-1 promotes immune evasion in tumors by facilitating the expression of programmed cell death-ligand 1.Front Immunol2024;15:1365894 PMCID:PMC11109370

[70]

Lin LL,Osmulski PA.PAI-1 uncouples integrin-β1 from restrain by membrane-bound β-catenin to promote collagen fibril remodeling in obesity-related neoplasms.Cell Rep2024;43:114527 PMCID:PMC11956528

[71]

Hendrikson J,Ng WH.Ligand-mediated PAI-1 inhibition in a mouse model of peritoneal carcinomatosis.Cell Rep Med2022;3:100526 PMCID:PMC8861959

[72]

Kortlever RM.Senescence, wound healing and cancer: the PAI-1 connection.Cell Cycle2006;5:2697-703

[73]

Chibaya L,Ruscetti M.Senescence and the tumor-immune landscape: Implications for cancer immunotherapy.Semin Cancer Biol2022;86:827-45 PMCID:PMC9357237

[74]

Lin LL,Lin CL.PAI-1-dependent inactivation of SMAD4-modulated junction and adhesion complex in obese endometrial cancer.Cell Rep2020;33:108253 PMCID:PMC7641039

[75]

Kubala MH.The plasminogen activator inhibitor-1 paradox in cancer: a mechanistic understanding.Cancer Metastasis Rev2019;38:483-92 PMCID:PMC7001780

[76]

Bastard J,Hainque B.Relationship between plasma plasminogen activator inhibitor 1 and insulin resistance.Diabetes Metab Res Rev2000;16:192-201

[77]

Nordt TK,Fujii S.Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo.Circulation1995;91:764-70

[78]

Dai W,Lund H.Intracellular tPA-PAI-1 interaction determines VLDL assembly in hepatocytes.Science2023;381:eadh5207 PMCID:PMC10697821

[79]

Levine JA,Eren M.Role of PAI-1 in hepatic steatosis and dyslipidemia.Sci Rep2021;11:430 PMCID:PMC7801442

[80]

Levine J,Eren M.OR22-6 reversal of diet induced metabolic syndrome in mice with an orally active small molecule inhibitor of PAI-1.J Endocr Soc2019;3:OR22-6 PMCID:PMC6554789

[81]

Donato AJ,Lesniewski LA.Mechanisms of dysfunction in the aging vasculature and role in age-related disease.Circ Res2018;123:825-48 PMCID:PMC6207260

[82]

Folsom AR,Wing RR.Impact of weight loss on plasminogen activator inhibitor (PAI-1), factor VII, and other hemostatic factors in moderately overweight adults.Arterioscler Thromb1993;13:162-9

[83]

Bareja A,Ho T.Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor Plg-R(KT).Cell Rep2024;43:113881 PMCID:PMC11075744

[84]

Hong SH.Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences.Int J Mol Sci2020;21:494 PMCID:PMC7013734

[85]

Silverthorn DU. Human physiology: an integrated approach. 2020. Available from: https://archive.org/details/humanphysiologyi0000silv_x2f9 [Last accessed on 22 Apr 2025]

[86]

Buchanan S,Stenvinkel P.Klotho, aging, and the failing kidney.Front Endocrinol2020;11:560 PMCID:PMC7481361

[87]

Kuro-o M,Aizawa H.Mutation of the mouse klotho gene leads to a syndrome resembling ageing.Nature1997;390:45-51

[88]

Hu MC,Zhang J.Klotho deficiency causes vascular calcification in chronic kidney disease.J Am Soc Nephrol2011;22:124-36 PMCID:PMC3014041

[89]

Eren M,Murphy SB.PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice.Proc Natl Acad Sci USA2014;111:7090-5 PMCID:PMC4024885

[90]

Kuro-O M.Klotho and aging.Biochim Biophys Acta2009;1790:1049-58 PMCID:PMC2743784

[91]

Gehlot P,Kaushik V.Unconventional localization of PAI-1 in PML bodies: a possible link with cellular growth of endothelial cells.Biochem Biophys Rep2024;39:101793 PMCID:PMC11332193

[92]

Furuya H,Chen R.PAI-1 is a potential transcriptional silencer that supports bladder cancer cell activity.Sci Rep2022;12:12186 PMCID:PMC9288475

[93]

Zhang D,Xu H.Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-κB p65 nuclear translocation.Mol Cancer2024;23:70 PMCID:PMC10993572

[94]

Fay WP,Condrey LR.Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene.Blood1997;90:204-8

[95]

Khan SS,Klyachko E.A null mutation in SERPINE1 protects against biological aging in humans.Sci Adv2017;3:eaao1617 PMCID:PMC5687852

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