Download PDF
Thromb Haemost 2004; 91(04): 674-682
DOI: 10.1160/TH03-06-0384
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Direct attenuation of plasminogen activator inhibitor type-1 expression in human adipose tissue by thiazolidinediones

Andreas Zirlik
1   Department of Cardiology, University of Freiburg, Freiburg, Germany
,
Anne Leugers
1   Department of Cardiology, University of Freiburg, Freiburg, Germany
,
Jens Lohrmann
1   Department of Cardiology, University of Freiburg, Freiburg, Germany
,
Sandra Ernst
1   Department of Cardiology, University of Freiburg, Freiburg, Germany
,
Burton E. Sobel
2   Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
,
Christoph Bode
1   Department of Cardiology, University of Freiburg, Freiburg, Germany
,
Thomas K. Nordt
1   Department of Cardiology, University of Freiburg, Freiburg, Germany
3   Department of Cardiology, Katharinenhospital, Klinikum Stuttgart, Stuttgart, Germany
› Author AffiliationsFinancial support: The present study was supported by a grant from Astra Zeneca (to T.K.N.).
Further Information

Publication History

Received 19 June 2003

Accepted after revision 21 January 2004

Publication Date:
06 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Adipose tissue produces substantial amounts of plasminogen activator inhibitor type-1 (PAI-1), an established cardiovascular risk factor. This study evaluated PAI-1 expression in human adipose tissue in response to thiazolidinediones, insulin sensitising drugs activating peroxisome proliferator-activated receptorgamma (PPAR-γ). Troglitazone, rosiglitazone, and ciglitazone significantly reduced PAI-1 protein expression in human preadipocytes under basal conditions and after stimulation of the cells with TGF-β. Pioglitazone had no effect. In human adipocytes all four thiazolidinediones significantly attenuated PAI-1 expression. Signalling appeared to be mediated via PPAR-γ and effects reflected, at least in part, changes in transcription. Accordingly, patients with insulin resistance may benefit from treatment with thiazolidinediones with respect to diminution of PAI-1 expression in adipose tissue and consequent potential reduction of cardiovascular risk.

Keywords

PAI-1 - adipose tissue - PPAR-γ - coronary heart disease - diabetes mellitus
 

  • References

  • 1 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-7.
    PubMedGoogle Scholar
  • 2 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.
    PubMedGoogle Scholar
  • 3 Margaglione M, Di Minno G, Grandone E. et al. Abnormally high circulation levels of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with a history of ischemic stroke. Arterioscler Thromb 1994; 14: 1741-5.
    CrossrefPubMedGoogle Scholar
  • 4 Meade TW, Ruddock V, Stirling Y. et al. Fibrinolytic activity, clotting factors, and long-term incidence of ischemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-9.
    CrossrefPubMedGoogle Scholar
  • 5 Juhan-Vague I, Roul C, Alessi MC. et al. Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients – relationship with plasma insulin. Thromb Haemost 1989; 61: 370-3.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor I levels: a possible link between insulin resistance and atherothrombosis. Diabetologia 1991; 34: 457-62.
    CrossrefPubMedGoogle Scholar
  • 7 Juhan-Vague I, Vague P, Alessi MC. et al. Relationships between plasma insulin, triglyceride, body mass index, and plasminogen inhibitor 1. Diabetes Metab 1987; 13: 331-6.
    PubMedGoogle Scholar
  • 8 Morange PE, Alessi MC, Verdier M. et al. PAI-1 produced ex vivo by human adipose tissue is relevant to PAI-1 blood level. Arterioscler Thromb Vasc Biol 1999; 19: 1361-5.
    CrossrefPubMedGoogle Scholar
  • 9 Lundgren CH, Brown SL, Nordt TK. et al. Elaboration of type-1 plasminogen activator inhibitor from adipocytes – a potential pathogenetic link between obesity and cardiovascular disease. Circulation 1996; 93: 106-10.
    CrossrefPubMedGoogle Scholar
  • 10 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: 860-7.
    CrossrefPubMedGoogle Scholar
  • 11 Birgel M, Gottschling-Zeller H, Röhrig K. et al. Role of cytokines in the regulation of plasminogen inhibitor-1 expression and secretion in newly differentiated subcutaneous human adipocytes. Arterioscler Thromb Vasc Biol 2000; 20: 1682-7.
    CrossrefPubMedGoogle Scholar
  • 12 Alessi MC, Bastelica D, Morange P. et al. Plasminogen activator inhibitor 1, transforming growth factor-β1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 2000; 49: 1374-80.
    CrossrefPubMedGoogle Scholar
  • 13 Eriksson P, Reynisdottir S, Lönnqvist F. et al. Adipose tissue secretion of plasminogen activator inhibitor-1 in non-obese and obese individuals. Diabetologia 1998; 41: 65-71.
    CrossrefPubMedGoogle Scholar
  • 14 Bastelica D, Morange P, Berthet B. et al. 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 2002; 22: 173-8.
    CrossrefPubMedGoogle Scholar
  • 15 Lehmann JM, Moore LB, Smith-Oliver TA. et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferatoractivated receptor gamma (PPAR gamma). J Biol Chem 1995; 270: 12953-6.
    CrossrefPubMedGoogle Scholar
  • 16 Nolan JJ, Ludvik B, Beerdsen P. et al. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994; 331: 1188-93.
    CrossrefPubMedGoogle Scholar
  • 17 Haffner SM, Greenberg AS, Weston WM. et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002; 106: 679-84.
    CrossrefPubMedGoogle Scholar
  • 18 Buchanan TA, Meehan WP, Jeng YY. et al. Blood pressure lowering by pioglitazone: evidence for a direct vascular effect. J Clin Invest 1995; 96: 354-60.
    CrossrefPubMedGoogle Scholar
  • 19 Barbier O, Torra IP, Duguay Y. et al. Pleiotropic actions of peroxisome proliferatoractivated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 2002; 22: 717-26.
    CrossrefPubMedGoogle Scholar
  • 20 Collins AR, Meehan WP, Kintscher U. et al. Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 2001; 21: 365-71.
    CrossrefPubMedGoogle Scholar
  • 21 Kruszynska YT, Yu JG, Olefsky JM. et al. Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects. Diabetes 2000; 49: 633-9.
    CrossrefPubMedGoogle Scholar
  • 22 Hauner H, Schmid P, Pfeiffer EF. Glucocorticoids and insulin promote the differentiation of human adipocyte precursor cells into fat cells. J Clin Endocrinol Metab 1987; 64: 832-5.
    CrossrefPubMedGoogle Scholar
  • 23 Gorzelniak K, Janke J, Engeli S. et al. Validation of endogenous controls for gene expression studies in human adipocytes and preadipocytes. Horm Metab Res 2001; 33: 625-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Meigs JB, Mittlermann MA, Nathan DM. et al. Hyperinsulinemia, hyperglycemia and impaired haemostasis. JAMA 2000; 283: 221-8.
    CrossrefPubMedGoogle Scholar
  • 25 Juhan-Vague I, Pyke S, Alessi MC. et al. Fibrinolytic factor and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation 1996; 94: 2057-63.
    CrossrefPubMedGoogle Scholar
  • 26 Folsom AR, Qamhieh HAT, Wing RR. et al. Impact of weight loss on plasminogen activator inhibitor (PAI-1), factor VII, and other haemostatic factors in moderately overweight adults. Arterioscler Thromb 1993; 13: 162-9.
    CrossrefPubMedGoogle Scholar
  • 27 Primrose JN, Davies JA, Prentice CRM. et al. Reduction in factor VII, fibrinogen and plasminogen activator inhibitor 1 activity after surgical treatment of morbid obesity. Thromb Haemost 1992; 68: 396-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Vestergraad H, Lund S, Pedersen O. Rosiglitazone treatment of patients with extreme insulin resistance and diabetes mellitus due to insulin receptor mutations has no effects on glucose and lipid metabolism. J Intern Med 2001; 250: 406-14.
    CrossrefPubMedGoogle Scholar
  • 29 Kliewer SA, Lenhard JM, Willson TM. et al. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 1995; 83: 813-9.
    CrossrefPubMedGoogle Scholar
  • 30 Nagy L, Tontonoz P, Alvarez JG. et al. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ. Cell 1998; 93: 229-40.
    CrossrefPubMedGoogle Scholar
  • 31 Henke BR, Blanchard SG, Brackeen MF. et al. N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem 1998; 41: 5020-36.
    CrossrefPubMedGoogle Scholar
  • 32 Adams M, Montague CT, Prins JB. et al. Activators of peroxisome proliferator-activated receptor γ have depot-specific effects on human preadipocyte differentiation. J Clin Invest 1997; 100: 3149-53.
    CrossrefPubMedGoogle Scholar
  • 33 Kallen CB, Lazar MA. Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes. Proc Natl Acad Sci USA 1996; 93: 5793-6.
    CrossrefPubMedGoogle Scholar
  • 34 Gottschling-Zeller H, Birgel M, Scriba D. et al. Depot-specific release of leptin from subcutaneous and omental adipocytes in suspension culture: effect of tumor necrosis factoralpha and transforming growth factor-beta1. Eur J Endocrinol 1999; 141: 436-42.
    CrossrefPubMedGoogle Scholar
  • 35 Nordt TK, Lutzi S, Ruef J. et al. Attenuation by fibrates of plasminogen activator inhibitor type-1 expression in human arterial smooth muscle cells. Thromb Haemost 2001; 86: 1305-13.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Nordt TK, Peter K, Bode C. et al. Differential regulation by troglitazone of plasminogen activator inhibitor type 1 in human hepatic and vascular cells. J Clin Endocrinol Metab 2000; 85: 1563-8.
    PubMedGoogle Scholar
  • 37 Katsuki A, Sumida Y, Murata K. et al. Troglitazone reduces plasma levels of tumour necrosis factor-alpha in obese patients with type 2 diabetes. Diabetes Obes Metab 2000; 02: 189-91.
    CrossrefPubMedGoogle Scholar
  • 38 Hamaguchi E, Takamura T, Shimizu A. et al. TNF-α and troglitazone regulate plasminogen activator inhibitor type 1 (PAI-1) production through ERK-and NF-κB-dependent pathways in cultured human umbilical vein endothelial cells. J Pharmacol Exp Ther 2003; 307: 987-94 Epub 2003 Oct. 08.
    CrossrefPubMedGoogle Scholar
  • 39 Ihara H, Urano T, Takada A. et al. Induction of plasminogen activator inhibitor 1 gene expression in adipocytes by thiazolidinediones. FASEB 2001; 1233-5.
    PubMedGoogle Scholar
  • 40 Tontonoz P, Hu E, Spiegelmann BM. Stimulation of adipogenesis in fibroblasts by PPAR-gamma 2, a lipid-activated transcription factor. Cell 1998; 93: 241-52.
    CrossrefPubMedGoogle Scholar
  • 41 He G, Pedersen SB, Bruun JM. et al. Metformin, but not thiazolidinediones, inhibits plasminogen activator inhibitor-1 production in human adipose tissue in vitro. Horm Metab Res 2003; 35: 18-23.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Gesta S, Lolmede K, Daviaud D. et al. Culture of human adipose tissue explants leads to profound alteration of adipocyte gene expression. Horm Metab Res 2003; 35: 158-63.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Kato K, Satoh H, Endo Y. et al. Thiazolidinediones downregulate plasminogen activator inhibitor type 1 expression in human vascular endothelial cells: a possible role for PPAR-γ in endothelial function. Biochem Biophys Res Commun 1999; 258: 431-5.
    CrossrefPubMedGoogle Scholar
  • 44 Marx N, Bourcier T, Sukhova GK. et al. PPARγ activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression. Arterioscler Thromb Vasc Biol 1999; 19: 546-51.
    CrossrefPubMedGoogle Scholar
  • 45 Hsueh WA, Law RE. PPARγ and atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21: 1891-5.
    CrossrefPubMedGoogle Scholar
  • 46 Li AC, Brown KK, Silvestre MJ. et al. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2000; 106: 523-31.
    CrossrefPubMedGoogle Scholar
  • 47 Minamikawa J, Tanaka S, Yamauchi M. et al. Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 1998; 83: 1818-20.
    CrossrefPubMedGoogle Scholar