Cardiovascular disease is the leading cause of morbidity and mortality in patients with obesity/type 2 diabetes. Strict glycemic control in recent large-scale clinical trials failed to demonstrate cardiovascular mortality benefit in type 2 diabetic patients. Novel strategies capable of protecting the heart against diabetes-exacerbated post- myocardial infarction (MI) remodeling are urgently needed. Research in the past decade has increased understanding of the roles adipocytes (ADp) play in health and disease. Functional ADp are critical in maintaining systemic metabolic hemostasis, whereas ADp dysfunction is one of the most recognized pathogenic factors leading to obesity/type 2 diabetes. The cardiomyocyte (CM) is the most important cell type maintaining heart function. Its failure is the direct cause of diabetic cardiac death. Complete understanding of the molecular mechanisms mediating the adverse communication between diabetic ADp (the culprit of obesity-induced diabetes) and diabetic CM (the victim in which injury most significantly contributes to diabetic cardiovascular death) will certainly help development of effective therapies against diabetic cardiovascular death. Extracellular vesicles, particularly exosomes (Exo), are critical agents in remote organ communication. Our most recently published study demonstrates for the first time that diabetes causes significant ADp Exo dysfunction, switching ADp-Exo from cargo-carrying cardioprotective molecules to vehicles delivering cardiotoxic molecules from ADp to CM, critically contributing to diabetic cardiac injury. Our preliminary data further demonstrate that diabetic CM lose protective response to non-diabetic ADp-Exo, while uptake of diabetic ADp-Exo significantly increases. Several in vivo and in vitro experiments strongly suggest that diabetes-induced CM adiponectin receptor-1 (AdipoR1) phosphorylation is a central mechanism switching Exo-mediated ADp-CM communication from a receptor/intracellular salvage kinase activation system to a vehicle delivering toxic ADp-Exo into diabetic CM, enhancing post-MI remodeling and accelerating heart failure. This novel hypothesis will be rigorously investigated by utilizing multiple tissue-specific genetically manipulated animals and pharmacological interventions. Specific Aim 1 will clarify the critical role of diabetes-induced CM AdipoR1 phosphorylation in blocking ADp-Exo mediated cardioprotection. Specific Aim 2 will test a hypothesis that diabetes-induced CM AdipoR1 phosphorylation promotes toxic ADp-Exo endocytosis. Specific Aim 3 will prove a concept that diabetes- induced CM AdipoR1 phosphorylation plays a causative role in diabetic ADp-Exo mediated cardiac injury. Successful completion of these studies will reveal a novel molecular mechanism responsible for diabetic exacerbation of cardiac injury, and potentially identify novel therapy against post-MI remodeling in diabetic patients. Moreover, successful completion of the proposed studies may...