Cav-3 in Diabetic Myocardial Injury Following Ischemia/Reperfusion

描述（由申请人提供）：随着2型糖尿病的患病率持续上升，迫切需要有效预防糖尿病心血管并发症的干预措施，糖尿病心血管并发症占该人群死亡人数的50%。糖尿病阻断心脏对多种促生存信号通路的反应，使心肌细胞更容易受到MI/R损伤。导致糖尿病心脏保护信号“普遍”损伤的分子机制尚不清楚。以cav为中心的信号复合体在促进快速、精确和协调的信号转导中起着至关重要的作用，广泛参与细胞保护和生存。然而，cav信号复合物是否以及如何改变并导致心脏保护信号的损害仍然未知。我们的初步实验表明，在2型糖尿病的早期发展阶段，Cav3的硝化修饰和由此导致的Cav3与其伴侣蛋白的解离发生，阻断了Cav3依赖的信号传导。目前的应用将验证一个假设，即在糖尿病心脏中，多种心脏保护干预所需的Cav3信号体由于特定Tyr残基的Cav3硝化修饰而受损，导致促进生存的心脏保护信号级联的普遍丧失，从而导致心肌梗死后糖尿病患者死亡率增加。并结合体外和体内方法来鉴定特定的酪氨酸残基，其硝化/氧化修饰导致心脏保护cav3信号体的分解（specific Aim 1），阻断其生物学功能（specific Aim 2），并揭示恢复糖尿病心脏中心脏保护信号的新治疗策略（specific Aim 3），最终目标是降低糖尿病个体的心血管死亡率。从本应用程序提出的研究中产生的新数据将定义

DESCRIPTION (provided by applicant): As the prevalence of type 2 diabetes continues to escalate, there is an urgent need for interventions that effectively prevent diabetic cardiovascular complications, which account for >50% of deaths in this population. Diabetes blocks the cardiac response to multiple prosurvival signaling pathways, rendering cardiomyocytes more susceptible to MI/R injury. The molecular mechanisms leading to "universal" impairment of cardioprotective signaling in the diabetic heart remain unclear. Cav-centered signaling complexes play essential roles in facilitating rapid, precise, and coordinated signal transduction broadly involved in cell protection and survival. However, whether and how Cav-signal complexes are altered and contribute to impairment of cardioprotective signaling remains unknown. Our preliminary experiments demonstrate that nitrative modification of Cav3 and resultant dissociation of Cav3 from its partner proteins occur during the early development phase of type 2 diabetes, blocking Cav3- dependent signaling. The current application will test a hypothesis that, in the diabetic heart, cardioprotective Cav3-signalsomes required by multiple cardioprotective interventions are impaired due to Cav3 nitrative modification at specific Tyr residue(s), resulting in the universal loss of prosurvival cardioprotective signaling cascades, contributing to increased diabetic patient mortality after MI. We will utilize advanced molecular/cellular technologies, and combine in vitro and in vivo approaches to identify the specific tyrosine residue(s) whose nitrative/oxidative modification results in disassembly of cardioprotective Cav3-signalsomes (Specific Aim 1), blocking their biological functions (Specific Aim 2), and reveal novel therapeutic strategies restoring cardioprotective signaling in the diabetic heart (Specific Aim 3), with the ultimate goal of reducing cardiovascular mortality in diabetic individuals. The novel data resulting from this application's proposed studies will define novel molecular mechanisms leading to the loss of cardioprotective response in diabetic heart, and potentially identify novel cardioprotective targets that may preserve/restore various cardioprotective signaling during early developmental diabetic stages.