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Plasminogen activator inhibitor links obesity and thrombotic cerebrovascular diseases: The roles of PAI-1 and obesity on stroke

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Abstract

One of the global socioeconomic phenomena occurred during the last decades is the increased prevalence of obesity, with direct consequence on the risk of developing thrombotic disorders. As the physiological inhibitor of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1) is well known for its role in fibrinolysis. More and more evidences have shown that PAI-1 involves in physiopathologic mechanisms of many diseases and metabolic disorder. Increased serum level of PAI-1 has been observed in obesity and it also contributes to the development of adipose tissue and then has effects on obesity. Meantime, obesity affects also the PAI-1 levels. These evidences indicate the complicated interaction between PAI-1 and obesity. Many clinic studies have confirmed that obesity relates to the stroke outcome although there are many contradictory results. Simultaneously, correlation is found between plasma PAI-1 and thrombotic cerebrovascular diseases. This article reviews contemporary knowledge regarding the complex interplay of obesity, PAI-1 and stroke.

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References

  • Ahn CW, Kim CS, Nam JH, Kim HJ, Nam JS, Park JS, Kang ES, Cha BS, Lim SK, Kim KR, Lee HC, Huh KB (2006) Effects of growth hormone on insulin resistance and atherosclerotic risk factors in obese type 2 diabetic patients with poor glycaemic control. Clin Endocrinol 64:444–449

    CAS  Google Scholar 

  • Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I (1997) Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 46:860–867

    Article  CAS  PubMed  Google Scholar 

  • Barba R, Marco J, Ruiz J, Canora J, Hinojosa J, Plaza S, Zapatero-Gaviria A (2015) The obesity paradox in stroke: impact on mortality and short-term readmission. J Stroke Cerebrovasc Dis 24:766–770

    Article  PubMed  Google Scholar 

  • Bastelica D, Morange P, Berthet B, Borghi H, Lacroix O, Grino M, Juhan-Vague I, Alessi MC (2002) Stromal cells are the main plasminogen activator inhibitor-1 producing cells in human fat: evidence of differences between visceral and subcutaneous deposits. Arterioscler Thromb Vasc Biol 22:173–178

    Article  CAS  PubMed  Google Scholar 

  • Cesari M, Pahor M, Incalzi RA (2010) Plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions. Cardiovasc Ther 28:e72–e91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cigolini M, Targher G, Bergamo Andreis IA, Tonoli M, Agostino G, De Sandre G (1996) Visceral fat accumulation and its relation to plasma hemostatic factors in healthy men. Arterioscler Thromb Vasc Biol 16:368–374

    Article  CAS  PubMed  Google Scholar 

  • Crandall DL, Quinet EM, Ayachi ES, Hreha AL, Leik CE, Savio DA, Juhan-Vague I, Alessi MC (2006) Modulation of adipose tissue development by pharmacological inhibition of PAI-1. Arterioscler Thromb Vasc Biol 26:2209–2215

    Article  CAS  PubMed  Google Scholar 

  • De Taeye BM, Novitskaya T, Gleaves L, Covington JW, Vaughan DE (2006) Bone marrow plasminogen activator inhibitor-1 influences the development of obesity. J Biol Chem 281:32796–32805

    Article  CAS  PubMed  Google Scholar 

  • Declerck PJ, Gils A (2013) Three decades of research on plasminoge n activator inhibitor-1: a multifaceted serpin. Semin Thromb Hemost 39:356–364

    Article  CAS  PubMed  Google Scholar 

  • Dehlendorff C, Andersen KK, Olsen TS (2014) Body mass index and death by stroke: no obesity paradox. JAMA Neurol 71:978–984

    Article  PubMed  Google Scholar 

  • Dichtl W, Ares MP, Stollenwerk M, Giachelli CM, Scatena M, Hamsten A, Eriksson P, Nilsson J (2000) In vivo stimulation of vascular plasminogen activator inhibitor-1 production by very low-density lipoprotein involves transcription factor binding to a VLDL-responsive element. Thromb Haemost 84:706–711

    CAS  PubMed  Google Scholar 

  • Eriksson P, Van Harmelen V, Hoffstedt J, Lundquist P, Vidal H, Stemme V, Hamsten A, Arner P, Reynisdottir S (2000) Regional variation in plasminogen activator inhibitor-1 expression in adipose tissue from obese individuals. Thromb Haemost 83:545–548

    CAS  PubMed  Google Scholar 

  • Fernandez-Cadenas I, Alvarez-Sabin J, Ribo M, Rubiera M, Mendioroz M, Molina CA, Rosell A, Montaner J (2007) Influence of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1gene polymorphisms on tissue-type plasminogen activator-induced recanalization in ischemic stroke patients. J Thromb Haemost 5:1862–1868

    Article  CAS  PubMed  Google Scholar 

  • Giacchetti G, Faloia E, Mariniello B, Sardu C, Gatti C, Camilloni MA, Guerrieri M, Mantero F (2002) Overexpression of the renin-angiotensin system in human visceral adipose tissue in normal and overweight subjects. Am J Hypertens 15:381–388

    Article  CAS  PubMed  Google Scholar 

  • Halleux CM, Deckerck PJ, Tran SL, Detry R, Brichard SM (1999) Hormonal control of plasminogen activator inhibitor-1 gene expression and production in adipose tissue: stimulation by glucocorticoids and inhibition by cathecholamines. J Clin Endocrinol Metab 84:4097–4105

    CAS  PubMed  Google Scholar 

  • He G, Pedersen SB, Bruun JM, Lihn AS, Jensen PF, Richelsen B (2003) Differences in plasminogen activator inhibitor 1 in subcutaneous versus omental adipose tissue in non-obese and obese subjects. Horm Metab Res 35:178–182

    Article  CAS  PubMed  Google Scholar 

  • Jankun J, Skrzypczak-Jankun E (2009) Yin and yang of the plasminogen activator inhibitor. Pol Arch Med Wewn 119:410–417

    CAS  PubMed  Google Scholar 

  • Johansson L, Jansson JH, Boman K, Nilsson TK, Stegmayr B, Hallmans G (2000) Tissue plasminogen activator, plasminogen activator inhibitor-1, and tissue plasminogen activator/ plasminogen activator inhibitor-1 complex as risk factors for the development of a first stroke. Stroke 31:26–32

    Article  CAS  PubMed  Google Scholar 

  • Kastorini CM, Panagiotakos DB (2012) The obesity paradox: methodological considerations based on epidemiological and clinical evidence--new insights. Maturitas 72:220–224

    Article  PubMed  Google Scholar 

  • Keric N, Maier GS, Samadani U, Kallenberg K, Dechent P, Brueck W, Heuer J, Rohde V (2012) Tissue plasminogen activator induced delayed edema in experimental porcine intracranial hemorrhage: reduction with plasminogen activator inhibitor-1 administration. Transl Stroke Res 3:88–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kernan WN, Inzucchi SE, Sawan C, Macko RF, Furie KL (2013) Obesity: a stubbornly obvious target for stroke prevention. Stroke 44:278–286

    Article  PubMed  Google Scholar 

  • Kim JW, Lee SH, Ko HM, Kwon KJ, Cho KS, Choi CS, Park JH, Kim HY, Lee J, Han SH, Ignarro LJ, Cheong JH, Kim WK, Shin CY (2011) Biphasic regulation of tissue plasminogen activator activity in ischemic rat brain and in cultured neural cells: essential role of astrocyte-derived plasminogen activator inhibitor-1. Neurochem Int 58:423–433

    Article  CAS  PubMed  Google Scholar 

  • Kim Y, Kim CK, Jung S, Yoon BW, Lee SH (2015) Obesity-stroke paradox and initial neurological severity. J Neurol Neurosurg Psychiatry 86:743–747

    Article  PubMed  Google Scholar 

  • Kindell DG, Keck RW, Jankun J (2015) Comparison between the clot-protecting activity of a mutant plasminogen activator inhibitor-1 with a very long half-life and 6-aminocaproic acid. Exp Ther Med 9:2339–2343

    CAS  PubMed  PubMed Central  Google Scholar 

  • Klaus S (2004) Adipose tissue as a regulator of energy balance. Curr Drug Targets 5:241–250

    Article  CAS  PubMed  Google Scholar 

  • Kurata A, Nishizawa H, Kihara S, Maeda N, Sonoda M, Okada T, Ohashi K, Hibuse T, Fujita K, Yasui A, Hiuge A, Kumada M, Kuriyama H, Shimomura I, Funahashi T (2006) Blockade of angiotensin II type-1 receptor reduces oxidative stress in adipose tissue and ameliorates adipocytokine dysregulation. Kidney Int 70:1717–1724

    Article  CAS  PubMed  Google Scholar 

  • Laumen H, Skurk T, Hauner H (2008) The HMG-CoA reductase inhibitor rosuvastatin inhibits plasminogen activator inhibitor-1 expression and secretion in human adipocytes. Atherosclerosis 196:565–573

    Article  CAS  PubMed  Google Scholar 

  • Le Lay S, Simard G, Martinez MC, Andriantsitohaina R (2014) Oxidative stress and metabolic pathologies: from an adipocentric point of view. Oxidative Med Cell Longev 2014:908539

    Article  Google Scholar 

  • Lijnen HR (2005) Effect of plasminogen activator inhibitor-1 deficiency on nutritionally-induced obesity in mice. Thromb Haemost 93:816–819

    CAS  PubMed  Google Scholar 

  • Lijnen HR, Maquoi E, Morange P, Voros G, Van Hoef B, Kopp F, Collen D, Juhan-Vague I, Alessi MC (2003) Nutritionally induced obesity is attenuated in transgenic mice overexpressing plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 23:78–84

    Article  CAS  PubMed  Google Scholar 

  • Lira FS, Rosa JC, Dos Santos RV, Venancio DP, Carnier J, Sanches Pde L, do Nascimento CM, de Piano A, Tock L, Tufik S, de Mello MT, Dâmaso AR, Oyama LM (2011) Visceral fat decreased by long-term interdisciplinary lifestyle therapy correlated positively with interleukin-6 andtumor necrosis factor-α and negatively with adiponectin levels in obese adolescents. Metabolism 60:359–365

    Article  CAS  PubMed  Google Scholar 

  • Loskutoff DJ, Samad F (1998) The adipocyte and hemostatic balance in obesity: studies of PAI-1. Arterioscler Thromb Vasc Biol 18:1–6

    Article  CAS  PubMed  Google Scholar 

  • Ma LJ, Mao SL, Taylor KL, Kanjanabuch T, Guan Y, Zhang Y, Brown NJ, Swift LL, McGuinness OP, Wasserman DH, Vaughan DE, Fogo AB (2004) Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes 53:336–346

    Article  CAS  PubMed  Google Scholar 

  • Mantovani RM, Rios DR, Moura LC, Oliveira JM, Carvalho FF, Cunha SB, Viana Mde F, Lamounier JA, Castro JC, Dusse LM, Simões e Silva AC (2011) Childhood obesity: evidence of an association between plasminogen activator inhibitor-1 levels and visceraladiposity. J Pediatr Endocrinol Metab 24:361–367

    Article  CAS  PubMed  Google Scholar 

  • Mavri A, Stegnar M, Krebs M, Sentocnik JT, Geiger M, Binder BR (1999) Impact of adipose tissue on plasma plasminogen activator inhibitor-1 in dieting obese women. Arterioscler Thromb Vasc Biol 19:1582–1587

    Article  CAS  PubMed  Google Scholar 

  • Morange PE, Aubert J, Pieretti F, Lijnen HR, Vague P, Verdier M, Négrel R, Juhan-Vague I, Alessi MC (1999) Glucocorticoids and insulin promote plasminogen activator inhibitor 1 production by human adipose tissue. Diabetes 48:890–895

    Article  CAS  PubMed  Google Scholar 

  • Morange PE, Lijnen HR, Alessi MC, Kopp F, Collen D, Juhan-Vague I (2000) Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet-induced obesity. Arterioscler Thromb Vasc Biol 20:1150–1154

    Article  CAS  PubMed  Google Scholar 

  • Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, DK MG, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB, American Heart Association Statistics Committee and Stroke Statistics Subcommittee (2016) Executive Summary: Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 133:447–454

    Article  PubMed  Google Scholar 

  • Nagai N, Suzuki Y, Van Hoef B, Lijnen HR, Collen D (2005) Effects of plasminogen activator inhibitor-1 on ischemic brain injury in permanent and thrombotic middle cerebral artery occlusion models in mice. J Thromb Haemost 3:1379–1384

    Article  CAS  PubMed  Google Scholar 

  • Neeland IJ, Ayers CR, Rohatgi AK, Turer AT, Berry JD, Das SR, Vega GL, Khera A, McGuire DK, Grundy SM, de Lemos JA (2013) Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults. Obesity (Silver Spring) 21:E439–E447

    CAS  Google Scholar 

  • Ny T, Sawdey M, Lawrence D, Millan JL, Loskutoff DJ (1986) Cloning and sequence of a cDNA coding for the human beta-migrating endothelial-cell-type plasminogen activator inhibitor. Proc Natl Acad Sci U S A 83:6776–6780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohkura N, Oishi K, Atsumi G (2015) Blood coagulation and metabolic profiles in middle-aged male and female ob/ob mice. Blood Coagul Fibrinolysis 26:522–526

    Article  CAS  PubMed  Google Scholar 

  • Oishi K, Koyanagi S, Matsunaga N, Kadota K, Ikeda E, Hayashida S, Kuramoto Y, Shimeno H, Soeda S, Ohdo S (2010) Bezafibrate induces plasminogen activator inhibitor-1 gene expression in a CLOCK-dependent circadian manner. Mol Pharmacol 78:135–141

    Article  CAS  PubMed  Google Scholar 

  • Olsen TS, Dehlendorff C, Petersen HG, Andersen KK (2008) Body mass index and poststroke mortality. Neuroepidemiology 30:93–100

    Article  PubMed  Google Scholar 

  • Orenes-Piñero E, Pineda J, Roldán V, Hernández-Romero D, Marco P, Tello-Montoliu A, Sogorb F, Valdés M, Lip GY, Marín F (2015) Effects of body mass index on the lipid profile and biomarkers of inflammation and a Fibrinolytic and Prothrombotic state. J Atheroscler Thromb 22:610–617

    Article  PubMed  Google Scholar 

  • Ovbiagele B, Bath PM, Cotton D, Vinisko R, Diener HC (2011) Obesity and recurrent vascular risk after a recent ischemic stroke. Stroke 42:3397–3402

    Article  PubMed  Google Scholar 

  • Pandey M, Tuncman G, Hotamisligil GS, Samad F (2003) Divergent roles for p55 and p75 TNF-alpha receptors in the induction of plasminogen activator inhibitor-1. Am J Pathol 162:933–941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Placencio VR, DeClerck YA (2015) Plasminogen activator inhibitor-1 in cancer: rationale and insight for future therapeutic testing. Cancer Res 75:2969–2674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pou KM, Massaro JM, Hoffmann U, Vasan RS, Maurovich-Horvat P, Larson MG, Keaney JF Jr, Meigs JB, Lipinska I, Kathiresan S, Murabito JM, O'Donnell CJ, Benjamin EJ, Fox CS (2007) Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart study. Circulation 116:1234–1241

    Article  CAS  PubMed  Google Scholar 

  • Ryu WS, Lee SH, Kim CK, Kim BJ, Yoon BW (2011) Body mass index, initial neurological severity and long-term mortality in ischemic stroke. Cerebrovasc Dis 32:170–176

    Article  PubMed  Google Scholar 

  • Samad F, Loskutoff DJ (1996) Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol Med 2:568–582

    CAS  PubMed  PubMed Central  Google Scholar 

  • Samad F, Ruf W (2013) Inflammation, obesity, and thrombosis. Blood 122:3415–3422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Samad F, Uysal KT, Wiesbrock SM, Pandey M, Hotamisligil GS, Loskutoff DJ (1999) Tumor necrosis factor alpha is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1. Proc Natl Acad Sci U S A 96:6902–6907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schäfer K, Fujisawa K, Konstantinides S, Loskutoff DJ (2001) Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice. FASEB J 15:1840–1842

    PubMed  Google Scholar 

  • Shin JA, Jeong SI, Kim M, Yoon JC, Kim HS, Park EM (2015) Visceral adipose tissue inflammation is associated with age-related brain changes and ischemic brain damage in aged mice. Brain Behav Immun 50:221–231

    Article  PubMed  Google Scholar 

  • Skurk T, Lee YM, Hauner H (2001) Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture. Hypertension 37:1336–1340

    Article  CAS  PubMed  Google Scholar 

  • Tjärnlund-Wolf A, Brogren H, Lo EH, Wang X (2012) Plasminogen activator inhibitor-1 and thrombotic cerebrovascular diseases. Stroke 43:2833–2839

    Article  PubMed  PubMed Central  Google Scholar 

  • Towfighi A, Ovbiagele B (2009) The impact of body mass index on mortality after stroke. Stroke 40:2704–2708

    Article  PubMed  Google Scholar 

  • Uchida Y, Ohba K, Yoshioka T, Irie K, Muraki T, Maru Y (2004) Cellular carbonyl stress enhances the expression of plasminogen activator inhibitor-1 in rat white adipocytes via reactive oxygen species-dependent pathway. J Biol Chem 279:4075–4083

    Article  CAS  PubMed  Google Scholar 

  • Van De Craen B, Declerck PJ, Gils A (2012) Glycosylation influences the stability of human plasminogen activator inhibitor-1. Blood Coagul Fibrinolysis 23:570–572

    Article  PubMed  Google Scholar 

  • Wang Z, Zeng X, Chen Z, Wang X, Zhang L, Zhu M, Yi D (2015) Association of visceral and total body fat with hypertension and prehypertension in a middle-aged Chinese population. J Hypertens 33:1555–1562

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto K, Takeshita K, Shimokawa T, Yi H, Isobe K, Loskutoff DJ, Saito H (2002) Plasminogen activator inhibitor-1 is a major stress-regulated gene: implications for stress-induced thrombosis in aged individuals. Proc Natl Acad Sci U S A 99:890–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamashiro K, Tanaka R, Tanaka Y, Miyamoto N, Shimada Y, Ueno Y, Urabe T, Hattori N (2014) Visceral fat accumulation is associated with cerebral small vessel disease. Eur J Neurol 21:667–673

    Article  CAS  PubMed  Google Scholar 

  • Yang D, Nemkul N, Shereen A, Jone A, Dunn RS, Lawrence DA, Lindquist D, Kuan CY (2009) Therapeutic administration of plasminogen activator inhibitor-1 prevents hypoxic-ischemic brain injury in newborns. J Neurosci 29:8669–8674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao R, Ma X, Shen GX (2008) Transcriptional regulation of plasminogen activator inhibitor-1 in vascular endothelial cells induced by oxidized very low density lipoproteins. Mol Cell Biochem 317:197–204

    Article  CAS  PubMed  Google Scholar 

  • Zhuang P, Wo D, Xu ZG, Wei W, Mao HM (2015) Dynamic changes in plasma tissue plasminogen activator, plasminogen activator inhibitor-1 and beta-thromboglobulin content in ischemic stroke. J Clin Neurosci 22:1123–1127

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81670405, 81370409, 81400208, 81400269), Natural Science Foundation of Jiangsu Province (BK20161355), Social Development Foundation of Zhenjiang (SH2014025) and Key Laboratory of Cardiovascular Disease of Zhenjiang (SS2012002).

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  1. Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China

    Rui Chen, Jinchuan Yan, Peijing Liu, Zhongqun Wang & Cuiping Wang

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  1. Rui Chen
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Chen, R., Yan, J., Liu, P. et al. Plasminogen activator inhibitor links obesity and thrombotic cerebrovascular diseases: The roles of PAI-1 and obesity on stroke. Metab Brain Dis 32, 667–673 (2017). https://doi.org/10.1007/s11011-017-0007-3

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