Abstract 9905: Nitrative Modification of Caveolin-3 and Subsequent Dissociation From AdipoR1 Occurs in Failing Heart and Contributes to Adiponectin Resistance
Cardiac response to adiponectin (APN), a cardioprotective molecule, is significantly reduced during heart failure (HF), due to unknown underlying mechanisms. We recently reported Caveolin-3 (Cav3) plays an essential role in APN signaling by holding AdipoR1 in close proximity with its downstream signaling molecules. The current study investigated whether Cav3/AdipoR1 expression and/or their interaction are altered in the failing heart, thereby contributing to APN resistance and HF progression. Adult male mice were subjected to MI. Molecular, biochemical, and functional assays were performed 2 weeks post-MI, a time point during which significant APN resistance develops. Expression (mRNA and protein) of Cav3, AdipoR1, and known intracellular APN signaling molecules remained unchanged. However, Cav3/AdipoR1 complex formation significantly decreased. Among multiple post-translational modifications observed in the failing heart, Cav3 nitrative modification was the most significant (3.57±0.4-fold, P<0.01). In vivo treatment with a peroxynitrite (ONOO-) decomposition catalyst reduced Cav3 nitration and restored Cav3/AdipoR1 association. In vitro exposure of adult cardiomyocytes (CM) to SIN-1 (an ONOO- donor) or authentic chemical ONOO- caused significant Cav3 nitration, reduced Cav3/AdipoR1 association, and blocked APN-induced AMPK phosphorylation (P<0.01). APN treatment significantly attenuated Ang-II induced neonatal CM hypertrophy (P<0.01). However, the anti-hypertrophic effect of APN was virtually abolished by knockout of either Cav3 or AdipoR1, or SIN-1 pre-treatment in CM. Finally, in neonatal CM isolated from Cav3KO mice transfected with WT Cav3 vector, SIN-1 caused significant Cav3 nitration, Cav3/AdipoR1 dissociation, and blocked APN-induced AMPK activation. In contrast, in neonatal CM isolated from Cav3KO mice transfected with mutated Cav3 (in which all 5 tyrosine residues were substituted by phenylalanine) vector, no Cav3 nitration was observed after SIN-1 exposure; Cav3/AdipoR1 association was maintained, and APN-induced AMPK activation was preserved. These results demonstrate Cav3 tyrosine residue modification during HF progression causes Cav3/AdipoR1 dissociation, blocking APN cardioprotection.
- © 2013 by American Heart Association, Inc.