Abstract 10955: Adiponectin Inhibits Oxidative/Nitrative Stress During Myocardial Ischemia and Reperfusion via PKA Signaling
Cardioprotection of adiponectin (APN) against myocardial ischemia/reperfusion (MI/R) injury has been well-documented. However, comprehension of the mechanisms mediating intracellular APN signaling remains incomplete. We recently demonstrate that antioxidant/antinitrative protection of APN is not mediated by AMPK. PKA has been previously demonstrated to interact with APN receptor 1, but with uncertain biological relevance. The current study investigated whether the anti-oxidative/anti-nitrative effect of APN is mediated by PKA. 48 hours after left ventricular free wall intramyocardial injection of PKA-siRNA (achieving 70% cardiac-specific PKA- knockdown) or scramble-siRNA (control), male adult WT or cardiac specific AMPKα2 dominant negative overexpression (AMPK-DN) mice were subjected to 30 minutes MI (via LAD ligation), followed by 3 (for caspase-3 activity) or 24 hours (for infarct size and cardiac function determination) R. Globular domain of APN (gAPN,2 µg/g) or vehicle was administered 10 minutes before R. There was no statistically significant difference between scramble or PKA-KD siRNA mice in apoptosis (caspase-3 activity), infarct size, or cardiac function. Importantly, PKA-KD significantly attenuated gAPN-reduction of measured oxidative (superoxide production: 4.38±0.17 vs 6.95±0.49 RLU/s/mg tissue, gp91 expression: 0.50±0.02 vs 0.83±0.04, all P<0.05) and nitrative (NO production:1.10±0.05 vs 1.37±0.07 nmol/mg protein, peroxynitrite formation:0.64±0.04 vs 1.04±0.05 pmol/mg protein, all P<0.05) stress post MI/R. Similar data was obtained in AMPK-DN mice. Moreover, MI/R-induced NFκB activation by IKK/IκB phosphorylation was significantly inhibited by gAPN in control (NFκB activity: 55.03±2.50 vs 36.45±3.15 ng/mg protein in MI/R and MI/R+gAPN, respectively). However, gAPN did not inhibit NFκB activity during PKA-knockdown (P>0.05).
Conclusion: Taken together, we demonstrate for the first time that APN inhibits oxidative/nitrative stress during myocardial ischemia and reperfusion via PKA signaling.
- © 2012 by American Heart Association, Inc.