Abstract 8961: Essential Role of Caveolin-3 in Adiponectin Signalsome Formation and Adiponectin Cardioprotection
Adiponectin (APN) is an adipocyte-derived cardioprotective molecule, and systemic APN malfunction is causatively related to increased cardiovascular morbidity/mortality in diabetic patients. Although several APN receptors and multiple cytosolic effector molecules have been identified, signaling mechanisms linking receptors with effectors remain largely undefined. Caveolin (Cav) interacts with multiple membrane/intracellular proteins and regulates transmembrane signaling. However, the role of Cav in APN signaling remains unknown. Our current study determined the role of Cav3 (the predominant Cav form in cardiomyocytes) in APN signaling and investigated the underlying molecular mechanisms. Compared to wild type (WT), Cav-3 knockout (Cav-3KO) mice exhibited modestly increased myocardial ischemia/reperfusion injury (increased infarct size, apoptosis, and poorer cardiac function recovery, P<0.05). Most importantly, the cardioprotective effects of APN observed in WT were either markedly reduced (P<0.01) or completely lost in Cav-3KO, although key APN signaling molecules, including APN receptors (AdipoRs), APPL1, and AMPK were normal in these animals. Molecular/cellular experiments revealed that AdipoR1 co-localizes with Cav-3, forming AdipoR1/Cav-3 complex via specific Cav-3 scaffolding domain binding motifs. AdipoR1/Cav-3 interaction is required for both APN-initiated AMPK-dependent and AMPK-independent intracellular cardioprotective signaling. Moreover, APPL1 and adenylate cyclase (AC), two immediately downstream molecules respectively requisite for AMPK-dependent and AMPK-independent signaling, form a protein complex with AdipoR1 in Cav-3 dependent fashion. Finally, in contrast to APN (which failed to cardioprotect in Cav-3KO mice), AICAR (an AMPK activator) and db-cAMP (a PKA activator) co-administration significantly reduced myocardial infarct size and improved cardiac function in Cav-3KO animals. These results demonstrated for the first time that Cav-3 is an essential molecule in the formation of a membrane-situated signalsome for APN transmembrane signaling. Pathological alteration in APN signalsome formation may impair APN transmembrane signaling and contribute to systemic APN malfunction.
- © 2011 by American Heart Association, Inc.