With continually improving reperfusion strategies, the overall mortality of AMI has been significantly reduced in non-diabetic patients. However, both the prevalence and severity of ischemic heart failure (IHF) continually escalate in patients with type 2 diabetes. Identifying risk factors, pathological mechanisms, and effective interventions blocking diabetic exacerbation of IHF are urgently needed. Endothelial injury and resultant coronary microvascular dysfunction (CMD) are the hallmarks of diabetic cardiovascular complications, hindering adequate reperfusion despite successful recanalization. Clarifying mechanisms responsible for diabetic CMD and identifying effective interventions improving coronary circulation are essential in reducing diabetic IHF exacerbation. 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 type 2 diabetes. A complete understanding of the molecular mechanisms mediating the communication between adipose tissue and heart will undoubtedly help the development of effective therapies against diabetic cardiovascular death. Extracellular vesicles, particularly exosomes (Exo), are increasingly recognized as systemic messengers mediating inter- cellular/inter-organ communication. Evidence from our recently published work and additional preliminary data strongly suggest that GRK5-induced coronary microcirculatory endothelial cells (CMEC) adiponectin receptor 1 (AdipoR1) phosphorylation is responsible for attenuated ADp-derived Exo (ADp-Exo) protective signaling and increased cytotoxic ADp-Exo uptake in diabetic CMEC, contributing to diabetic exacerbation of CMD and IHF. Targeting the GRK5-AdipoR1 system may be a novel therapeutic intervention against diabetic CMD, ultimately protecting the heart against IHF. This novel hypothesis will be rigorously investigated in 3 specific aims. Utilizing genetic gain- and loss-of-function approaches, Specific Aim 1 will test a hypothesis that diabetes-induced CMEC AdipoR1 phosphorylation blocks ADp-Exo mediated vasculoprotection, contributing to diabetic CMD and IHF exacerbation. Specific Aim 2 will test a novel hypothesis that diabetic AdipoR1 phosphorylation and resultant endocytosis promotes CMEC uptake of cytotoxic ADp-Exo via adiponectin (on ADp-Exo surface) interaction with AdipoR1 (expressed in CMEC). Specific Aim 3 will determine whether 1) EC AdipoR1 phosphorylation mediates diabetic ADp-Exo induced CMD and IHF, and 2) blocking EC AdipoR1 phosphorylation is effective in protecting diabetes-exacerbated CMD and IHF. Successful completion of these studies will reveal a novel molecular mechanism responsible for the diabetic exacerbation of cardiovascular injury, and potentially identify novel therapy against CMD and post-MI remodeling in diabetic patients. Moreover, succ...