Abstract 547: Essential Role of Adiponectin in Rosiglitazone’s Cardioprotection against Myocardial Ischemic Injury
The favorable metabolic effects in patients treated with peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist are associated with increase in plasma adiponectin (ADN). However, the role of ADN in PPAR-γ agonist’s therapeutic actions remains unclear. We and others recently reported that PPAR-γ agonists and ADN both reduce myocardial ischemic (MI) injury. However, the relationship between these two molecules in concerning their cardioprotetcion has never been previously investigated. Adult male wild type (WT) and ADN knockout (KO-ADN) mice (n=12–15 mice/group) were treated with vehicle (V) or rosiglitazone (RSG, 10 mg/kg/day) for 7 or 10 (for survival rate only) days and their coronary artery was ligated 3 days after starting the treatment. Four days after MI, adipocyte ADN mRNA expression, plasma ADN and glucose levels, lipid profiles, cardiac function, myocardial infarct size, and myocardial apoptosis and protein nitration in non-ischemic area were determined. Treatment with RSG had no effect on plasma glucose or lipid profiles in either WT or KO-ADN mice. Treatment of WT mice, but not KO-ADN mice, with RSG significantly increased adipocyte ADN expression and elevated plasma ADN level (1.8- and 2.3-fold vs. V, P<0.05). RSG treatment in WT mice reduced infarct size (37±2.5 vs. 51±4.1% in V, P<0.01), decreased caspase-3 activity (0.9±0.13 vs. 1.6±0.18 U/mg protein/h, P<0.01), attenuated protein nitration (4.2±0.23 vs. 5.8±0.26 nmol/g protein, P<0.05) and improved cardiac function (measured by ±dp/dtmax and LVEDP, P<0.05). In strict contrast, treatment of KO-ADN mice with RSG had no effect on infarct size (59±8.7 vs. 62±5.6% in V), apoptosis (2.0±0.7 vs. 2.3±0.5 U/mg protein/h), protein nitration (6.2±0.9 vs. 6.6±0.5 nmol/g protein) and cardiac function. Finally, treatment with RSG significantly improved survival rate in WT (73.3% vs. 54.5%) but not in KO-ADN mice (38.4% vs. 32.1%). Collectively, we have provided the first direct evidence that ADN plays an essential role in PPAR-γ agonists’ cardioprotection against MI injury. These data suggest that under pathologic conditions where ADN expression is impaired (such as type 2 diabetes), supplementation of ADN may be more effective than PPAR-γ agonists in protecting heart against MI injury.