Abstract 557: Exosome Biogenesis/Uptake Mediates Cardioprotection by Globular Adiponectin but Not High Molecular Weight Adiponectin

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Objectives: Adiponectin, a multifunction adipokine with established cardioprotective effect, presents in high molecular weight (HMW) and globular isotype (gAPN). Recent study demonstrated that HMW cardioprotection depends on T-Cadherin (TCad). However, whether TCad also mediates the cardioprotective effects of gAPN, an isotype with much greater biological activity and wildly utilized in metabolic/cardiovascular investigations, remains unclear. Methods and results: Adult male WT, AdipoR1KO and TCadKO mice were subjected to MI, treated with vehicle or gAPN, and followed for 4 weeks. Knockout of AdipoR1, but not Tcad, abolished the cardioprotective effects of gAPN observed in WT mice, indicating that AdipoR1 but not Tcad mediates gAPN cardioprotection. Unexpectedly, we observed that gAPN cardioprotection was significantly attenuated when animals were pre-treated with GW4869, suggesting exosome involvement. To further delineate whether gAPN regulates exosome biogenesis and/or uptake and which stage is mediated by AdipoR1, cardiomyocytes were isolated from adult AdipoR1KO and TCadKO mice. Effects of gAPN and HMW upon exosome generation and uptake were evaluated. Surprisingly, cardiomyocyte exosome production was dramatically increased (8-fold) when cells were treated with gAPN but not with HMW (at 5-fold concentration of gAPN). Moreover, gAPN increases cardiomyocyte exosome production in a receptor-independent fashion and is achieved by regulating ESCRT-multivesicular body (MVB) pathway. However, gAPN stimulated exosome uptake and cellular protection observed in WT cardiomyocytes was abolished in AdipoR1KO-derived but no TCadKO-derived cardiomyocytes. Conclusions: These data demonstrated that gAPN and HMW cardioprotection exhibits different receptor dependence and is mediated by distinct mechanisms. HMW protects heart via binding with TCad. However, gAPN has a unique ability, promoting exosome biogenesis in a receptor-independent fashion and stimulating exosome uptake and cardioprotection in an AdipoR1-dependent manner. These results indicate that gAPN is superior to HMW in concerning cardioprotection against ischemia heart injury, and is a promising therapeutic strategy in patients with coronary artery disease.