on October 11, 2007
Published online before print October 11, 2007, doi: 10.1161/ATVBAHA.107.152462
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Submitted on May 25, 2007
Accepted on September 28, 2007
Adiponectin Mediates the Suppressive Effect of Rosiglitazone on Plasminogen Activator Inhibitor-1 Production
Ruby L.C. Hoo ;
From the Department of Medicine (R.L.C.H., W.S.C., M.H.Y., A.X., A.W.K.T., H.F.T., C.H.Y.F., K.S.L.L.) and the Research Centre of Heart, Brain, Hormone, and Healthy Aging (A.X., H.F.T., S.T., K.S.L.L.), LKS Faculty of Medicine, The University of Hong Kong, China; the Clinical Biochemistry Unit (S.T.), Queen Mary Hospital, Hong Kong, China; and the Division of Diabetes, Endocrinology, and Metabolism (L.C.), Departments of Medicine and Molecular & Cellular Biology, Baylor College of Medicine, Houston, Tex.
* To whom correspondence should be addressed. E-mail: ksllam{at}hkucc.hku.hk.
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 (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.
Key words: obesity • hyperglycemia • adipokines • thrombotic dieases
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