RAGE, Diabetes and Myocardial Infarction

描述（由申请人提供）：我们实验室的早期研究已经揭示了心肌梗死中的关键作用，因为与野生型小鼠相比，在离体灌注心脏中缺血/再灌注（I/R）后或左前降支（LAD）冠状动脉闭塞/再灌注后，全局缺失心肌梗死导致心肌坏死减少，功能恢复增加和ATP保存增加。在影响心脏对I/R损伤的反应的多种细胞类型中广泛表达，例如单核细胞/巨噬细胞、内皮细胞和心肌细胞。心肌缺血/再灌注导致氧化应激，并影响伴随心脏损伤的线粒体功能障碍。在本申请中，我们将使用鼠模型，在没有和存在糖尿病的情况下，探测由心脏中的I/R引起的炎症、血管和心肌细胞应激之间的“串扰”。我们的总体假设是，单核细胞/巨噬细胞、内皮细胞和心肌细胞中的信号转导总体上对受损的心脏非常有害。我们预测在I/R中，单核细胞/巨噬细胞产生破坏性介质，破坏有效愈合，RAGE依赖性内皮应力，特别是在糖尿病中，阻碍有效重塑。最后，我们预测I/R后小鼠心脏中高度上调的心肌细胞凋亡在愈合心肌中发出破坏性代谢后果的信号，其部分通过GSK-3b和凋亡事件触发线粒体功能障碍。我们实验室的两项新发现表明，mDia-1，一个同源结构域蛋白家族的成员和RhoGTPases的效应子，以及ROCK 1信号通路在RAGE介导的心血管应激中的作用。在本申请中，我们将探索RAGE依赖性mDia-1和/或ROCK信号传导在心脏中的作用。只有充分了解心肌梗死中细胞特异性β-受体信号的潜在适应性作用，以及该受体在I/R中刺激的邻近信号级联，才能实现β-受体拮抗作用的最佳设计。 公共卫生相关性：我们实验室的早期研究已经揭示了心肌梗死中的关键作用，因为全局缺失导致心肌坏死减少，功能恢复增加和心脏能量代谢的保护。拟议的研究将探索RAGE依赖性mDia-1和/或ROCK信号传导在心脏中介导心肌梗死后损伤的完整背景下的作用。只有充分了解心肌梗死中细胞特异性β-受体信号的潜在适应性作用，以及该受体在梗死中刺激的邻近信号级联，才能实现β-受体拮抗作用的最佳设计。

DESCRIPTION (provided by applicant): Earlier studies from our laboratory have uncovered key roles for RAGE in myocardial infarction, as global deletion RAGE resulted in decreased myocardial necrosis, increased functional recovery and preservation of ATP compared to wild-type mice after ischemia/reperfusion (I/R) in the isolated perfused heart or after occlusion/reperfusion of the left anterior descending (LAD) coronary artery. RAGE is expressed broadly in multiple cell types that impact on the heart's response to I/R injury, such as monocytes/macrophages, endothelial cells and cardiomyocytes. RAGE contributes to oxidative stress consequent to I/R and influences mitochondrial dysfunction that accompanies injury to the heart. In this application, we will probe the "cross- talk" between inflammatory, vascular and cardiomyocyte stresses evoked by I/R in the heart using murine models, both in the absence and presence of diabetes. Our overall hypothesis is that RAGE signaling in monocytes/macrophages, endothelial cells and cardiomyocytes is, overall, highly detrimental to the injured heart. We predict that in I/R, monocytes/macrophages produce damaging mediators that disrupt effective healing and that RAGE-dependent endothelial stress, particularly in diabetes, thwarts effective remodeling. Lastly, we predict that cardiomyocyte RAGE, highly upregulated in the murine heart after I/R, signals devastating metabolic consequences in the healing myocardium, which trigger mitochondrial dysfunction, in part through GSK-3b and apoptotic events. Two novel findings in our laboratory suggest roles for mDia-1, a member of the formin homology domain protein family and an effector of RhoGTPases, and the ROCK 1 signaling pathway in RAGE-mediated cardiovascular stress. In this application, we will probe the role of RAGE in the full context of RAGE-dependent mDia-1 and/or ROCK signaling in the heart. Only by a full understanding of potentially adaptive roles for cell-specific RAGE signaling in myocardial infarction, and the proximate signaling cascades stimulated by this receptor in I/R, will the optimal design of RAGE antagonism be achieved. PUBLIC HEALTH RELEVANCE: Earlier studies from our laboratory have uncovered key roles for RAGE in myocardial infarction, as global deletion RAGE resulted in decreased myocardial necrosis, increased functional recovery and preservation of energy metabolism in hearts. The proposed studies will probe the role of RAGE in the full context of RAGE-dependent mDia-1 and/or ROCK signaling in the heart that mediates injury after myocardial infarction. Only by a full understanding of potentially adaptive roles for cell-specific RAGE signaling in myocardial infarction, and the proximate signaling cascades stimulated by this receptor in infarction, will the optimal design of RAGE antagonism be achieved.