Download PDF
Thromb Haemost 2002; 88(03): 481-487
DOI: 10.1055/s-0037-1613241
Review Article
Schattauer GmbH

Relationships between Fibrinolytic and Inflammatory Parameters in Human Adipose Tissue: Strong Contribution of TNFα Receptors to PAI-1 Levels

Delphine Bastelica
1   Lab oratory of Hematology, EPI 99-36, Faculty of Medicine, Marseille, France
,
Alenka Mavri
2   University Medical Centre, Department of Angiology, Ljubljana, Slovenia
,
Monique Verdier
1   Lab oratory of Hematology, EPI 99-36, Faculty of Medicine, Marseille, France
,
Bruno Berthet
3   Department of Gastric Surgery, CHU Timone, Marseille, France
,
Irène Juhan-Vague
1   Lab oratory of Hematology, EPI 99-36, Faculty of Medicine, Marseille, France
,
Marie-Christine Alessi
1   Lab oratory of Hematology, EPI 99-36, Faculty of Medicine, Marseille, France
› Author Affiliations
Further Information

Publication History

Received 16 December 2001

Accepted after resubmission 28 May 2002

Publication Date:
08 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Plasminogen activator inhibitor type 1 (PAI-1), a risk marker of atherosclerosis, is highly expressed in adipose tissue from obese subjects. PAI-1 is also considered as an acute phase protein. Recently, adipose tissue has been described as a source of inflammatory cytokines. Therefore, our aim was to study the relationships between PAI-1, and IL-6, TNF, TNF receptors (TNFRSF1s) and TGFβ1, in plasma and adipose tissue from obese (n = 60) and lean (n = 28) subjects. Study has been extended to plasminogen activators (t-PA and u-PA).

Compared to lean subjects, obese subjects exhibited higher plasma levels of all the studied parameters (except for TGFβ1) whereas in adipose tissue only PAI-1, t-PA and TGFβ1 antigen levels differed. In the obese population, plasma PAI-1 levels were weakly associated with circulating TNF, and this relationship disappeared after adjustment for plasma t-PA. Adipose tissue PAI-1 levels were positively associated with TNFRSF1s and TGFβ1, the strongest relationship being observed with TNFRSF1A, which explained 82% of PAI-1 variability. TNF and IL-6 were the main contributors to t-PA variability in plasma and in adipose tissue, respectively.

Our results argue on the relevance of TNFRSF1s in the regulation of PAI-1 expression by adipose tissue. Association between t-PA, which is mainly produced by endothelial cells, and IL-6 or TNF suggest that inflammation might be involved in angiogenesis in adipose tissue.

Abbreviations: act: activity; ag: antigen; BMI: Body mass index; IL-6: Interleukin-6; PAI-1: plasminogen activator inhibitor type 1; TGFβ1: Transforming Growth Factor beta 1; TNF: Tumor Necrosis Factor alpha; TNFRSF1A and 1B: Tumor Necrosis Factor receptor superfamilly 1A and 1B (TNFRI and II respectively); t-PA: tissue type plasminogen activator; u-PA: urokinase type plasminogen activator

Keywords

Human adipose tissue - PAI-1 - Plasminogen activators - Inflammatory cytokines
 

  • References

  • 1 Vassalli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest 1991; 88: 1067-72.
    CrossrefPubMedGoogle Scholar
  • 2 Juhan-Vague I, Alessi MC. Regulation of fibrinolysis in the development of atherothrombosis: role of adipose tissue. Thromb Haemost 1999; 82: 832-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Juhan-Vague I, Pyke DM, Alessi MC, Jespersen J, Haverkate F, Thompson SG. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation 1996; 94: 2057-63.
    CrossrefPubMedGoogle Scholar
  • 4 Samad F, Loskutoff DJ. Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol Med 1996; 02: 568-82.
    PubMedGoogle Scholar
  • 5 Eriksson P, Reynisdottir S, Lônnqvist F, Stemme V, Hamsten A, Arner P. Adipose tissue secretion of plasminogen activator inhibitor-1 in non-obese and obese individuals. Diabetologia 1998; 41: 65-71.
    CrossrefPubMedGoogle Scholar
  • 6 Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I. 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
  • 7 Cigolini M, Tonoli M, Borgato L, Frigotto L, Manzato F, Zeminian S, Cardinale C, Camin M, Chiaramonte E, De Sandre G, Lunardi C. Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-alpha?. Atherosclerosis 1999; 143: 81-90.
    CrossrefPubMedGoogle Scholar
  • 8 Eriksson P, Van Harmelen V, Hoffstedt J, Lundquist P, Vidal H, Stemme V, Hamsten A, Arner P, Reynisdottir S. Regional variation in plasmainogen activator inhibitor-1 expression in adipose tissue from obese individuals. Thromb Haemost 2000; 83: 545-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K, Tokunaga K, Matsuzawa Y. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med 1996; 27: 800-3.
    PubMedGoogle Scholar
  • 10 Alessi MC, Bastelica D, Morange P, Berthet B, Leduc I, Verdier M, Geel O, Juhan-Vague I. Plasminogen activator inhibitor 1, transforming growth factor beta 1 and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 2000; 49: 1374-80.
    CrossrefPubMedGoogle Scholar
  • 11 Schafer K, Fujisawa K, Konstantinides S, Loskutoff DJ. 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 2001; 15: 1840-2.
    CrossrefPubMedGoogle Scholar
  • 12 Morange PE, Lijnen HR, Alessi MC, Kopp F, Collen D, Juhan-Vague I. Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet-induced obesity. Arterioscler Thromb Vasc Biol 2000; 20: 1150-4.
    CrossrefPubMedGoogle Scholar
  • 13 Vague P, Juhan-Vague I, Aillaud MF, Badier C, Viard R, Alessi MC, Collen D. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level and relative body weight in normal and obese subjects. Metabolism 1986; 03: 250-3.
    PubMedGoogle Scholar
  • 14 Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999; 282: 2131-5.
    CrossrefPubMedGoogle Scholar
  • 15 Festa A, D’Agostino Jr R, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000; 102: 42-7.
    CrossrefPubMedGoogle Scholar
  • 16 Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K, Chrousos GP. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 1997; 82: 1313-6.
    CrossrefPubMedGoogle Scholar
  • 17 Cook DG, Mendall MA, Whincup PH, Carey IM, Ballam L, Morris JE, Miller GJ, Strachan DP. C-reactive protein concentration in children: relationship to adiposity and other cardiovascular risk factors. Atherosclerosis 2000; 149: 139-50.
    CrossrefPubMedGoogle Scholar
  • 18 Lemieux I, Pascot A, Prud’homme D, Almeras N, Bogaty P, Nadeau A, Bergeron J, Despres JP. Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol 2001; 21: 881-3.
    CrossrefPubMedGoogle Scholar
  • 19 Samad F, Uysal KT, Wiesbrock SM, Pandey M, Hotamisligil GS, Loskutoff DJ. Tumor necrosis factor alpha is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1. Proc Natl Acad Sci 1999; 96: 6902-7.
    CrossrefPubMedGoogle Scholar
  • 20 Morange PE, Alessi MC, Verdier M, Casanova D, Magalon G, JuhanVague I. 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
  • 21 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
    CrossrefPubMedGoogle Scholar
  • 22 Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995; 332: 635-41.
    CrossrefPubMedGoogle Scholar
  • 23 de Maat MP, Dooijewaard G, Meijer P, Binder BR, Keber D, Risberg B, Kluft C, Jespersen J. Urokinase-type plasminogen activator system predicts risk of cardiovascular events in patients with angina pectoris: results of the ECAPTURE study. European Concerted Action on Prevention from Thrombosis by Urokinase Enhancement. Blood Coagul Fibrinolysis 2001; 12: 453-8.
    CrossrefPubMedGoogle Scholar
  • 24 van Hinsbergh VW, van den Berg EA, Fiers W, Dooijewaard G. Tumor necrosis factor induces the production of urokinase-type plasminogen activator by human endothelial cells. Blood 1990; 75: 1991-8.
    PubMedGoogle Scholar
  • 25 Falcone DJ, McCaffrey TA, Haimovitz-Friedman A, Garcia M. Transforming growth factor-beta 1 stimulates macrophage urokinase expression and release of matrix-bound basic fibroblast growth factor. J Cell Physiol 1993; 155: 595-605.
    CrossrefPubMedGoogle Scholar
  • 26 Sitter T, Toet K, Fricke H, Schiffl H, Held E, Kooistra T. Modulation of procoagulant and fibrinolytic system components of mesothelial cells by inflammatory mediators. Am J Physiol 1996; 271: R1256-63.
    CrossrefPubMedGoogle Scholar
  • 27 Darras V, Thienpont M, Stump DC, Collen D. Measurement of urokinase type plasminogen activator (u-PA) with an enzyme-linked immunosorbent assay (ELISA) based on three murine monoclonal antibodies. Thromb Haemost 1986; 56: 411-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-9.
    CrossrefPubMedGoogle Scholar
  • 29 Maniatis T, Fristsch EF, Sambrook J. Molecular cloning: A laboratory Manual. 2nd ed.. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1989: 9.16-9.19.
    Google Scholar
  • 30 Krasnikova TL, Parfyonova Y, Alekseeva IA, Arefieva TI, Mukhina SA, Dobrovolsky AB, Titaeva Y, Lyakishev AA, Resink TJ, Erne P, Tkachuk VA. Urokinase plasminogen activator system in humans with stable coronary artery disease. Clin Exp Pharmacol Physiol 1999; 26: 354-357.
    CrossrefPubMedGoogle Scholar
  • 31 Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?. Arterioscler Thromb Vasc Biol 1999; 19: 972-8.
    CrossrefPubMedGoogle Scholar
  • 32 Bertin E, Nguyen P, Guenounou M, Durlach V, Potron G, Leutenegger M. Plasma levels of tumor necrosis factor-alpha (TNF-alpha) are essentially dependent on visceral fat amount in type 2 diabetic patients. Diabetes Metab 2000; 26: 178-82.
    PubMedGoogle Scholar
  • 33 Corica F, Allegra A, Corsonello A, Buemi M, Calapai G, Ruello A, Nicita VMauro, Ceruso D. Relationship between plasma leptin levels and the tumor necrosis factor-alpha system in obese subjects. Int J Obes Relat Metab Disord 1999; 23: 355-60.
    CrossrefPubMedGoogle Scholar
  • 34 Mohamed-Ali V, Goodrick S, Bulmer K, Holly JM, Yudkin JS, Coppack SW. Production of soluble tumor necrosis factor receptors by human subcutaneous adipose tissue in vivo. Am J Physiol 1999; 277: E971-E975.
    PubMedGoogle Scholar
  • 35 Tsigos C, Kyrou I, Chala E, Tsapogas P, Stavridis JC, Raptis SA, Katsilambros N. Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity. Metabolism 1999; 48: 1332-5.
    CrossrefPubMedGoogle Scholar
  • 36 Straub RH, Hense HW, Andus T, Scholmerich J, Riegger GA, Schunkert H. Hormone replacement therapy and interrelation between serum interleukin6 and body mass index in postmenopausal women: a population-based study. J Clin Endocrinol Metab 2000; 85: 1340-4.
    CrossrefPubMedGoogle Scholar
  • 37 Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, Vidal H, Hainque B. Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab 2000; 85: 3338-42.
    PubMedGoogle Scholar
  • 38 Hauner H, Bender M, Haastert B, Hube F. Related plasma concentrations of soluble TNF-alpha receptors in obese subjects. Int J Obes Relat Metab Disord 1998; 22: 1239-943.
    CrossrefPubMedGoogle Scholar
  • 39 Fernandez-Real JM, Broch M, Ricart W, Casamitjana R, Gutierrez C, Vendrell J, Richart C. Plasma levels of the soluble fraction of tumor necrosis factor receptor 2 and insulin resistance. Diabetes 1998; 47: 1757-62.
    CrossrefPubMedGoogle Scholar
  • 40 Hotamisligil GS, Arner P, Atkinson RL, Spiegelman BM. Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance. Diabetes 1997; 46: 451-5.
    CrossrefPubMedGoogle Scholar
  • 41 Chandler WL, Alessi MC, Aillaud MF, Henderson P, Vague P, JuhanVague I. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels. Circulation 1997; 96: 761-8.
    CrossrefPubMedGoogle Scholar
  • 42 Haverkate F, Thompson SG, Duckert F. Haemostasis factors in angina pectoris; relation to gender, age and acute-phase reaction. Results of the ECAT Angina Pectoris Study Group. Thromb Haemost 1995; 04: 561-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Juhan-Vague I, Thompson SG, Jespersen J. Involvement of the hemostatic system in the insulin resistance syndrome. Arterioscl Thromb 1993; 13: 1865-73.
    CrossrefPubMedGoogle Scholar
  • 44 Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 2001; 280: E745-E751.
    CrossrefPubMedGoogle Scholar
  • 45 Bastard JP, Jardel C, Delattre J, Hainque B, Bruckert E, Oberlin F. Evidence for a link between adipose tissue interleukin-6 content and serum Creactive protein concentrations in obese subjects. Circulation 1999; 99: 2221-2.
    PubMedGoogle Scholar
  • 46 Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 1995; 95: 2111-9.
    CrossrefPubMedGoogle Scholar
  • 47 Koistinen HA, Bastard JP, Dusserre E, Ebeling P, Zegari N, Andreelli F, Jardel C, Donner M, Meyer L, Moulin P, Hainque B, Riou JP, Laville M, Koivisto VA, Vidal H. Subcutaneous adipose tissue expression of tumour necrosis factor-alpha is not associated with whole body insulin resistance in obese nondiabetic or in type-2 diabetic subjects. Eur J Clin Invest 2000; 30: 302-10.
    CrossrefPubMedGoogle Scholar
  • 48 Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995; 95: 2409-15.
    CrossrefPubMedGoogle Scholar
  • 49 Schreyer SA, Chua SC, LeBoeuf RC. Obesity and diabetes in TNF-alpha deficient mice. J Clin Invest 1999; 102: 402-11.
    PubMedGoogle Scholar