Relationship between IL-6, Leptin and Adiponectin and Variables of Fibrinolysis in Overweight and Obese Hypertensive Patients

Abstract

Impaired fibrinolysis is a common finding in obese humans. This condition is now considered as an established risk factor for thromboembolic complications. Furthermore, obesity is characterized by a specific pattern of circulating concentrations of fat-cell products interleukin-6 (IL-6), leptin, and adiponectin. The aim of our study was to investigate the relationship between these proteins and selected variables of the fibrinolytic system in 74 mildly hypertensive, overweight subjects. Circulating IL-6 and leptin levels showed a positive association with BMI (r = 0.24, p = 0.04 and r = 0.70, p < 0.0001), whereas adiponectin was not correlated to BMI. Interestingly, IL-6 was also positively associated with t-PA/PAI-1 complexes after adjustment for BMI and other anthropometric variables. Leptin was positively correlated with PAI-1 activity and antigen (r = 0.32, p = 0.006 and r = 0.37, p < 0.001, respectively) and negatively with t-PA activity (r = -0.27, p = 0.03). However, these associations lost significance after correction for BMI or HOMA, an insulin sensitivity index. In contrast, adiponectin levels were independently and negatively correlated with PAI-1 antigen (r = -0.26, p = 0.04, after correction for BMI). In conclusion, our study provides further evidence that IL-6, leptin, and adiponectin are associated with impaired fibrinolysis in overweight hypertensive humans.

Fibrinolysis - Obesity - Interleukin-6 - Leptin - Adiponectin

References

• 1 Mutch N J, Wilson H M, Booth N A. Plasminogen activator inhibitor-1 and haemostasis in obesity.  Proc Nutr Soc. 2001;  60 341-347
• 2 Mertens I, van Gaal L F. Obesity, haemostasis and the fibrinolytic system.  Obes Rev. 2002;  3 85-101
• 3 Juhan-Vague I, Alessi M C. PAI-1, obesity, insulin resistance and risk of cardiovascular events.  Thromb Haemost. 1997;  78 656-660
• 4 Juhan-Vague I, Pyke S D, Alessi M C, Jespersen J, Haverkate F, Thompson S G. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities.  Circulation. 1996;  94 2057-2063
• 5 Alessi M C, 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;  46 860-867
• 6 Eriksson P, Reynisdottir S, Lönnqvist 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
• 7 Gottschling-Zeller H, Birgel M, Röhrig K, Hauner H. Effect of tumor necrosis factor alpha and transforming growth factor beta 1 on plasminogen activator inhibitor-1 secretion from subcutaneous and omental human fat cells in suspension culture.  Metabolism. 2000;  49 666-671
• 8 Halleux C M, Declerck P J, Tran S L, Detry R, Brichard S. 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
• 9 Skurk T, Lee Y M, Hauner H. Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture.  Hypertension. 2001;  37 1336-1340
• 10 Birgel M, Gottschling-Zeller H, Röhrig K, Hauner H. 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
• 11 van der Meer I, de Maat M P, Bots M L, Breteler M M, Meijer J, Kiliaan A J. et al . Inflammatory mediators and cell adhesion molecules as indicators of severity of atherosclerosis: the Rotterdam Study.  Arterioscler Thromb Vasc Biol. 2002;  22 838-842
• 12 Blake G J, Ridker P M. Novel clinical markers of vascular wall inflammation.  Circ Res. 2001;  89 763-771
• 13 Ridker P M, Rifai N, Stampfer M J, Hennekens C H. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.  Circulation. 2000;  101 1767-1772
• 14 Fried S K, Bunkin D A, Greenberg A S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.  J Clin Endocrinol Metab. 1998;  83 847-850
• 15 Päth G, Bornstein S R, Gurniak M, Chrousos G P, Scherbaum W A, Hauner H. Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by beta-adrenergic activation and effects of IL-6 on adipocyte function.  J Clin Endocrinol Metab. 2001;  86 2281-2288
• 16 Stangl K, Cascorbi I, Laule M, Stangl V, Vogt M, Ziemer S. et al . Elevated serum leptin in patients with coronary artery disease: no association with the Trp64Arg polymorphism of the beta3-adrenergic receptor.  Int J Obes Relat Metab Disord. 2000;  24 369-375
• 17 Söderberg S, Ahren B, Jansson J H, Johnson O, Hallmans G, Asplund K, Olsson T. Leptin is associated with increased risk of myocardial infarction.  J Intern Med. 1999;  246 409-418
• 18 Wallace A M, McMahon A D, Pachard C J, Kelly A, Shepherd J, Gaw A, Sattar N. Plasma leptin and the risk of cardiovascular disease in the West of Scotland Coronary Prevention Study (WOSCOPS).  Circulation. 2001;  104 3052-3056
• 19 Berg A H, Combs T P, Scherer P E. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism.  Trends Endocrinol Metab. 2002;  13 84-89
• 20 Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y. et al . Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.  Arterioscler Thromb Vasc Biol. 2000;  20 1595-1599
• 21 Matthews D R, Hosker J P, Rudenski A S, Naylor B A, Treacher D F, Turner R C. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
• 22 Mohamed-Ali V, Goodrick S, Rawesh A, Miles J M, Katz D, Yudkin J S, Coppack S W. Human subcutaneous adipose tissue secretes interleukin-6 but not tumor necrosis factor-α in vivo.  J Clin Endocrinol Metab. 1997;  82 4196-4200
• 23 Owensby D A, Morton P A, Schwartz A L. Interactions between tissue-type plasminogen activator and extracellular matrix-associated plasminogen activator inhibitor type 1 in the human hepatoma cell line HepG2.  J Biol Chem. 1989;  264 18 180-18 187
• 24 Hoffmeister H M, Jur M, Helber U, Fischer M, Heller W, Seipel L. Correlation between coronary morphology and molecular markers of fibrinolysis in unstable angina pectoris.  Atherosclerosis. 1999;  144 151-157
• 25 Chandler W L, Alessi M C, Aillaud M F, Henderson P, Vague P, Juhan-Vague 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;  96 761-768
• 26 Söderberg S, Olsson T, Eliasson M, Johnson O, Ahren B. Plasma leptin levels are associated with abnormal fibrinolysis in men and postmenopausal women.  J Intern Med. 1999;  245 533-543
• 27 Okamoto Y, Arita Y, Nishida M, Muraguchi M, Ouchi N, Takahashi M. et al . An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls.  Horm Metab Res. 2000;  32 47-50