Stimulated in vivo synthesis of plasminogen activator inhibitor-1 in human adipose tissue

Mattias Ekström; Jan Liska; Per Eriksson; Eva Sverremark-Ekström; Per Tornvall

doi:10.1160/TH11-11-0822

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 108(03): 485-492
DOI: 10.1160/TH11-11-0822

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Stimulated in vivo synthesis of plasminogen activator inhibitor-1 in human adipose tissue

Mattias Ekström

¹Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden

,

Jan Liska

²Department of Cardiovascular Surgery and Anestesiology, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden

,

Per Eriksson

³Atherosclerosis Research Unit, Centre for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden

,

Eva Sverremark-Ekström

⁴Department of Immunology, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden

,

Per Tornvall

¹Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden

› Author Affiliations

Abstract

Summary

Plasminogen activator inhibitor type-1 (PAI-1) is one of the most important inhibitors of endogenous fibrinolysis. Adipose tissue is a suggested source of the elevated plasma levels of PAI-1 in obesity. The relation between PAI-1 and inflammation is of particular interest, but current knowledge regarding regulation of PAI-1 in adipose tissue is mainly based on animal studies or ex vivo experiments on human cultured adipocytes. So far, no study has described stimulated gene expression and protein synthesis of PAI-1 in vivo in human adipose tissue. We used open heart surgery as a model of acute systemic inflammation. Twenty-two male patients underwent blood sampling and omental and subcutaneous adipose tissue biopsies for gene expression studies before and after surgery. Expression and localisation of PAI-1 antigen was evaluated by immunohistochemistry. After surgery gene expression of PAI-1 increased 27-fold in omental adipose tissue and three-fold in subcutaneous adipose tissue, but no differences were found in tissue-type plasminogen activator (t-PA) mRNA. PAI-1 antigen was localised within endothelial cells and in the adipose tissue interstitium close to vessels. The upregulated gene expression and protein synthesis in adipose tissue was followed by increased concentrations of PAI-1 antigen in plasma. In conclusion, we present for the first time that an acute systemic inflammation in humans increased gene expression and protein synthesis of PAI-1 in adipose tissue and that this increase was most prominent in omental adipose tissue. PAI-1 synthesis in adipose tissue due to acute systemic inflammation may be a link between inflammation and impaired endogenous fibrinolysis.

Keywords

Adipose tissue - CABG - inflammation - PAI-1

Full Text

References

References
1 Gorog DA. Prognostic value of plasma fibrinolysis activation markers in cardiovascular disease. J Am Coll Cardiol 2010; 55: 2701-2709.
2 Rijken DC, Lijnen HR. New insights into the molecular mechanisms of the fibrinolytic system. J Thromb Haemost 2009; 07: 4-13.
3 Janand-Delenne B, Chagnaud C, Raccah D. et al. Visceral fat as a main determinant of plasminogen activator inhibitor 1 level in women. Int J Obes Relat Metab Disord 1998; 22: 312-317.
4 Shimomura I, Funahashi T, Takahashi M. et al. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med 1996; 02: 800-803.
5 Mertens I, Van der Planken M, Corthouts B. et al. Visceral fat is a determinant of PAI-1 activity in diabetic and non-diabetic overweight and obese women. Horm Metab Res 2001; 33: 602-607.
6 Kruithof EK. Regulation of plasminogen activator inhibitor type 1 gene expression by inflammatory mediators and statins. Thromb Haemost 2008; 100: 969-975.
7 Birgel M, Gottschling-Zeller H, Rohrig K. et al. Role of cytokines in the regulation of plasminogen activator inhibitor-1 expression and secretion in newly differentiated subcutaneous human adipocytes. Arterioscler Thromb Vasc Biol 2000; 20: 1682-1687.
8 Fain JN, Madan AK. Insulin enhances vascular endothelial growth factor, interleukin-8, and plasminogen activator inhibitor 1 but not interleukin-6 release by human adipocytes. Metabolism 2005; 54: 220-226.
9 Halleux CM, Declerck PJ, Tran SL. et al. Hormonal control of plasminogen activator inhibitor-1 gene expression and production in human adipose tissue: stimulation by glucocorticoids and inhibition by catecholamines. J Clin Endocrinol Metab 1999; 84: 4097-4105.
10 Plomgaard P, Keller P, Keller C. et al. TNF-alpha, but not IL-6, stimulates plasminogen activator inhibitor-1 expression in human subcutaneous adipose tissue. J Appl Physiol 2005; 98: 2019-2023.
11 Rega G, Kaun C, Weiss TW. et al. Inflammatory cytokines interleukin-6 and oncostatin m induce plasminogen activator inhibitor-1 in human adipose tissue. Circulation 2005; 111: 1938-1945.
12 Samad F, Yamamoto K, Loskutoff DJ. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. Induction by tumor necrosis factor-alpha and lipopolysaccharide. J Clin Invest 1996; 97: 37-46.
13 Sawdey MS, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysac-charide, tumor necrosis factor-alpha, and transforming growth factor-beta. J Clin Invest 1991; 88: 1346-1353.
14 Skurk T, Lee YM, Hauner H. Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture. Hypertension 2001; 37: 1336-1340.
15 Pralong G, Calandra T, Glauser MP. et al. Plasminogen activator inhibitor 1: a new prognostic marker in septic shock. Thromb Haemost 1989; 61: 459-462.
16 Alessi MC, Poggi M, Juhan-Vague I. Plasminogen activator inhibitor-1, adipose tissue and insulin resistance. Curr Opin Lipidol 2007; 18: 240-245.
17 Akkus MN, Polat G, Yurtdas M. et al. Admission levels of C-reactive protein and plasminogen activator inhibitor-1 in patients with acute myocardial infarction with and without cardiogenic shock or heart failure on admission. Int Heart J 2009; 50: 33-45.
18 Hamsten A, de Faire U, Walldius G. et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 02: 3-9.
19 Marcucci R, Brogi D, Sofi F. et al. PAI-1 and homocysteine, but not lipoprotein (a) and thrombophilic polymorphisms, are independently associated with the occurrence of major adverse cardiac events after successful coronary stenting. Heart 2006; 92: 377-381.
20 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408.
21 Aoki K, Nishino N, Baba S. et al. Postoperative changes in plasma tissue-type plasminogen activator and type 1 plasminogen activator inhibitor. Surg Today 1994; 24: 1039-1043.
22 Samama CM, Thiry D, Elalamy I. et al. Perioperative activation of hemostasis in vascular surgery patients. Anesthesiology 2001; 94: 74-78.
23 Sayer JW, Gutteridge C, Syndercombe-Court D. et al. Circadian activity of the endogenous fibrinolytic system in stable coronary artery disease: effects of beta-adrenoreceptor blockers and angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 1998; 32: 1962-1968.
24 Brull DJ, Sanders J, Rumley A. et al. Impact of angiotensin converting enzyme inhibition on post-coronary artery bypass interleukin 6 release. Heart 2002; 87: 252-255.
25 Tsai CS, Chen DL, Lin SJ. et al. TNF-alpha inhibits toll-like receptor 4 expression on monocytic cells via tristetraprolin during cardiopulmonary bypass. Shock 2009; 32: 40-48.
26 Ekstrom M, Halle M, Bjessmo S. et al. Systemic inflammation activates the nuclear factor-kappaB regulatory pathway in adipose tissue. Am J Physiol Endocrinol Metab 2010; 299: E234-240.
27 Alessi MC, Peiretti F, Morange P. et al. Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 1997; 46: 860-867.
28 Mestries JC, Kruithof EK, Gascon MP. et al. In vivo modulation of coagulation and fibrinolysis by recombinant glycosylated human interleukin-6 in baboons. Eur Cytokine Netw 1994; 05: 275-281.
29 Pretorius M, Murphey LJ, McFarlane JA. et al. Angiotensin-converting enzyme inhibition alters the fibrinolytic response to cardiopulmonary bypass. Circulation 2003; 108: 3079-3083.
30 Gottschling-Zeller H, Birgel M, Rohrig K. et al. Effect of tumor necrosis factor alpha and transforming growth factor beta 1 on plasminogen activator in-hibitor-1 secretion from subcutaneous and omental human fat cells in suspension culture. Metabolism 2000; 49: 666-671.
31 Eriksson P, Van Harmelen V, Hoffstedt J. et al. Regional variation in plasminogen activator inhibitor-1 expression in adipose tissue from obese individuals. Thromb Haemost 2000; 83: 545-548.
32 Vohl MC, Sladek R, Robitaille J. et al. A survey of genes differentially expressed in subcutaneous and visceral adipose tissue in men. Obes Res 2004; 12: 1217-1222.
33 Lindeman JH, Pijl H, Toet K. et al. Human visceral adipose tissue and the plasminogen activator inhibitor type 1. Int J Obes 2007; 31: 1671-1679.
34 Yudkin JS, Coppack SW, Bulmer K. et al. Lack of evidence for secretion of plasminogen activator inhibitor-1 by human subcutaneous adipose tissue in vivo. Thromb Res 1999; 96: 1-9.
35 Yusuf S, Hawken S, Ounpuu S. et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005; 366: 1640-1649.
36 Auerbach AD, Goldman L. beta-Blockers and reduction of cardiac events in noncardiac surgery: scientific review. J Am Med Assoc 2002; 287: 1435-1444.
37 Smeeth L, Thomas SL, Hall AJ. et al. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004; 351: 2611-2618.
38 Corrales-Medina VF, Madjid M, Musher DM. Role of acute infection in triggering acute coronary syndromes. Lancet Infect Dis 2010; 10: 83-92.
39 Eren M, Painter CA, Atkinson JB. et al. Age-dependent spontaneous coronary arterial thrombosis in transgenic mice that express a stable form of human plasminogen activator inhibitor-1. Circulation 2002; 106: 491-496.
40 Moor E, Blomback M, Silveira A. et al. Haemostatic function in patients undergoing coronary artery bypass grafting: peroperative perturbations and relations to saphenous vein graft closure. Thromb Res 2000; 98: 39-49.
41 Declerck PJ, Alessi MC, Verstreken M. et al. Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 1988; 71: 220-225.