Abstract 11301: AdipoRon, the First Orally Active Adiponectin Receptor Activator, Attenuates Myocardial Ischemia/Reperfusion Injury by AMPK-Mediated Autophagy and AMPK-Independent Anti-Apoptosis
Adiponectin (APN) is a cardioprotective molecule. Its reduction in diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury. Although APN administration in animals attenuates MI/R injury, multiple factors limit its clinical application. The current study investigated whether AdipoRon, the first orally active molecule binding APN receptors, may protect against cardiac MI/R injury, and if so, to delineate the mechanisms involved. Wild type (WT) or gene manipulated mice were treated with vehicle or AdipoRon (50 mg/kg, 10 min prior to MI) and subjected to MI/R (30 min/3-24 hours). Orally administered AdipoRon in WT mice significantly reduced infarct size and improved cardiac function (P<0.01), to a degree comparably observed in mice treated with intravenous APN. MI/R injury was significantly enhanced in mice deficient of either APN (APNKO) or AMPK (AMPK-DN). In APNKO mice, AdipoRon attenuated MI/R injury to the same degree observed in WT. In AMPK-DN mice, AdipoRon-mediated cardioprotection is partially inhibited. Mechanistically, AdipoRon inhibited oxidative/nitrative stress and apoptotic cell death in WT, APNKO, and AMPK-DK mice (P<0.01 vs. vehicle) to a comparable degree (NS among AdipoRon treated groups), indicating that AdipoRon exerts its anti-oxidative/anti-nitrative and anti-apoptotic effect via APMK-independent signaling. Moreover, MI/R significantly increased the LC3II/LC3I ratio (1.6-fold, P<0.01) which was not altered when autophagy clearance was inhibited by chloroquine co-treatment, suggesting that autophagy formation is increased but its clearance is inhibited. AdipoRon treatment further increased the LC3II/LC3I ratio (2.5-fold) and restored LAMP2 expression. Importantly, chloroquine administration almost doubled the LC3II/LC3I ratio (4.6-fold) in AdipoRon treated mice, indicating AdipoRon not only stimulates autophagy formation, but also increases its clearance. Finally, in AMPK-DN mice, AdipoRon-stimulated autophagy was markedly (though not completely) decreased. Collectively, these results demonstrate for the first time that an orally active APN receptor activator attenuates MI/R injury via AMPK-mediated autophagy and AMPK-independent anti-apoptotic means.
Author Disclosures: Y. Wang: None. R. Li: None. W. Lau: None. G. Liu: None. Y. Yuan: None. T. Christopher: None. B. Lopez: None. E. Gao: None. W. Koch: None. X. Ma: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.