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Adiponectin: An Indispensable Molecule in Rosiglitazone Cardioprotection Following Myocardial Infarction

Rationale: Patients treated with peroxisome proliferator-activated receptor (PPAR)-&ggr; agonist manifest favorable metabolic profiles associated with increased plasma adiponectin (APN). However, whether increased APN production as a result of PPAR-&ggr; agonist treatment is an epiphenomenon or is causatively related to the cardioprotective actions of PPAR-&ggr; remains unknown. Objective: To determine the role of APN in rosiglitazone (RSG) cardioprotection against ischemic heart injury. Methods and Results: Adult male wild-type (WT) and APN knockdown/knockout (APN+/− and APN−/−) mice were treated with vehicle or RSG (20 mg/kg per day), and subjected to coronary artery ligation 3 days after beginning treatment. In WT mice, RSG (7 days) significantly increased adipocyte APN expression, elevated plasma APN levels (2.6-fold), reduced infarct size (17% reduction), decreased apoptosis (0.23±0.02% versus 0.47±0.04% TUNEL-positive in remote nonischemic area), attenuated oxidative stress (48.5% reduction), and improved cardiac function (P<0.01). RSG-induced APN production and cardioprotection were significantly blunted (P<0.05 versus WT) in APN+/−, and completely lost in APN−/− (P>0.05 versus vehicle-treated APN−/− mice). Moreover, treatment with RSG for up to 14 days significantly improved the postischemic survival rate of WT mice (P<0.05 versus vehicle group) but not APN knockdown/knockout mice. Conclusions: The cardioprotective effects of PPAR-&ggr; agonists are critically dependent on its APN stimulatory action, suggesting that under pathological conditions where APN expression is impaired (such as advanced type 2 diabetes), the harmful cardiovascular effects of PPAR-&ggr; agonists may outweigh its cardioprotective benefits.