Diabetic Upregulation Of Grk2 Impairs Adipocyte Exosome Surface Adiponectin-mediated Cardioprotection And Exacerbates Ischemic Heart Failure

Background: Type 2 diabetes mellitus (DM) significantly exacerbates ischemic heart failure (IHF) by incompletely understood mechanisms. We recently reported that DM switches adipocyte-derived exosome (Exo) from cardioprotective signaling activators in nondiabetes (ND) to vehicles carrying cytotoxic molecules from DM adipocyte to heart. However, it remains unclear how DM triggers this switch and whether blocking it can protect against DM exacerbation of IHF. Methods and Results: ND or DM (12 weeks of high-fat diet) mice were subjected to MI/R (90 minutes/4 weeks) and treated with Exo (isolated from ND epidydimal fat pads and intramyocardially injected immediately before reperfusion). Exo administration significantly attenuated IHF in ND but not in DM mice. In vitro mechanistic and in vivo concept-prove experiments were conducted to determine how Exo protects against IHF and how DM blocks this protection. In cardiomyocytes (CM) from ND mice, Exo rapidly activated multiple injury salvage kinases (ISKs, including ERK, AMPK, and ACC) and attenuated cell death, suggesting that Exo-surface molecules mediate Exo cardioprotection. Exo-Flow (a method specifically detects Exo surface molecules) experiments demonstrated that adipocyte-derived Exo carries high levels of adiponectin (APN) on their surface. APN antibody-neutralized Exo or APNKO mice-derived Exo neither activated ISKs nor attenuated IHF. Exo failed to activate ISKs and protect IHF in AdipoR1KO mice. These results demonstrated that the adipocyte Exo surface-localized APN and CM-expressed AdipoR1 are essential in protective communication between adipocyte and heart. GRK2, a kinase that phosphorylates AdipoR1 at S205 and blocks APN cardioprotection, was dramatically upregulated in DM hearts. GRK2 overexpression blocked Exo-induced ISKs activation and cellular protection in WT CM but not in AdipoR1 S205A knock-in CM. Finally, Exo administration in AAV9-mediated CM-specific AdipoR1 S205A knock-in mice significantly attenuated diabetic IHF, while it failed to protect in AdipoR1 S205E mice. Conclusions: This study sheds light on the mechanisms underlying DM exacerbation of IHF and highlights the potential of targeting the APN/AdipoR1/GRK2 axis to protect against this condition.