Adiponectin mediates the suppressive effect of rosiglitazone on plasminogen activator inhibitor-1 production.

Author(s): Hoo RL, Chow WS, Yau MH, Xu A, Tso AW, Tse HF, Fong CH, Tam S, Chan L, Lam KS

Affiliation(s): Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China.

Publication date & source: 2007-12, Arterioscler Thromb Vasc Biol., 27(12):2777-82. Epub 2007 Oct 11.

Publication type: Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

OBJECTIVE: The purpose of this study was to examine the effects of PPAR-gamma 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 (n=64) 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, P=0.002). 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 (P<0.001), but this suppressive effect was attenuated in adiponectin knockout mice. Adenovirus-mediated 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 antithrombotic effect of rosiglitazone is mediated, at least in part, through the suppressive effect of adiponectin on PAI-1 production.