Adiponectin Mediates the Suppressive Effect of Rosiglitazone on Plasminogen Activator Inhibitor-1 Production

Abstract

Objective-The purpose of this study was to examine the effects of PPAR-␥ agonist rosiglitazone, relative to sulfonylureas, on circulating levels of adiponectin and the prothrombotic factor, plasminogen activator inhibitor (PAI)-1, in type 2 diabetic patients, and to investigate, in animal models, whether the antithrombotic action of rosiglitazone was mediated through adiponectin. Methods and Results-Our clinical study (nϭ64) showed that after 24-week add-on therapy, the rosiglitazone group had a greater mean reduction in plasma PAI-1 levels (25%, versus 12% in sulfonylurea group, Pϭ0.002).Stepwise multiple linear regression analysis identified the reduction in plasma fasting glucose and the rise in adiponectin levels to be independently associated with the reduction in PAI-I concentration in the rosiglitazone-treated patients. Rosiglitazone (20 mg/kg/d) reduced adipose tissue PAI-1 mRNA expression and its plasma levels in wild-type C57 mice with diet-induced obesity (PϽ0.001), but this suppressive effect was attenuated in adiponectin knockout mice. Adenovirusmediated overexpression of adiponectin led to a significant suppression of adipose tissue PAI-1 expression and its circulating concentrations in db/db diabetic mice. Our in vitro study demonstrated that recombinant adiponectin directly inhibited PAI-1 production in 3T3-L1 adipocytes. Conclusions-The

Adiponectin

“…On day zero of the experiment, mice were randomized to receive vehicle (control), rosiglitazone (RSG, 20 mg/kg/day25, oral gavage, Cayman Chemical, Ann Arbor, Michigan), MnTE-2-PyP 5+ (a cell permeable SOD mimic, 10 mg/kg/day, IP27) or RSG+MnTE-2-PyP 5+ (to determine the possible involvement of superoxide in RSG cardiac signaling). Seventy two hours after the first drug administration, mice were anesthetized with 2% isoflurane, and myocardial ischemia (MI) was produced by temporarily exteriorizing the heart via a left thoracic incision, and ligation of the left anterior descending (LAD) coronary artery with a 6-0 silk suture.…”

“…Treatment with PPARγ agonists stimulates APN production in adipocytes, and APN is the mediator through which PPARγ agonists achieve their insulin sensitization and metabolic benefits23. Moreover, recent experimental studies have demonstrated that APN plays an essential role in both the hepatic insulin sensitization and the plasminogen-activator-inhibitor-1 production suppressive effect of PPARγ agonists24,25. However, whether increased APN production as a result of PPARγ agonist treatment is solely an epiphenomenon, or is causatively related to PPAR-γ’s cardioprotective actions remains completely unknown.…”

Mitochondrial dysfunction contributes to the increased vulnerabilities of adiponectin knockout mice to liver injury†

“…Adiponectin knock-out (ADN-KO) mice in C57BL/6J background and the leptin receptor (Lepr) −/− /adiponectin −/− double knockout (DKO) mice were generated as we described recently (19). UCP2 knockout (UCP2-KO) mice in C57BL/6J background were purchased from the Jackson Laboratory (Bar Harbor, ME).…”

The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases

“…101 in addition, administration of adiponectin inhibits Pai-1 production in 3t3-l1 adipocytes and adenovirus-mediated over expression of adipo nectin suppresses Pai-1 expression in diabetic db/db mice. 101 However, PParγ ligands increased Pai-1 mrna and protein expression in human endothelial cells. 108 the inhibition of Pai-1 expression by lipid-lowering agents perhaps occurs because lipoprotein induces Pai-1 upregula tion.…”