RAGE, Diabetes and Myocardial Infarction

描述(申请人提供)：我们实验室的早期研究揭示了RAGE在心肌梗死中的关键作用，因为与野生型小鼠相比，在离体灌流心缺血/再灌流(I/R)或左前降支(LAD)阻断/再灌流后，RAGE全局缺失导致心肌坏死减少，功能恢复和ATP的保存增加。RAGE广泛表达于多种影响心脏对I/R损伤反应的细胞类型，如单核/巨噬细胞、内皮细胞和心肌细胞。RAGE促进了I/R引起的氧化应激，并影响伴随着心脏损伤的线粒体功能障碍。在这项应用中，我们将使用小鼠模型，在没有糖尿病和存在糖尿病的情况下，探索由心脏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/巨噬细胞、内皮细胞和心肌细胞中的RAGE信号总体上对受损心脏非常有害。我们预测，在I/R中，单核/巨噬细胞产生破坏有效愈合的破坏性介质，并且RAGE依赖的内皮应激，特别是在糖尿病中，阻碍有效的重塑。最后，我们预测心肌细胞RAGE在I/R后在小鼠心脏中高度上调，在愈合的心肌中发出破坏性的代谢后果的信号，这在一定程度上通过GSK-3b和凋亡事件引发线粒体功能障碍。我们实验室的两个新发现表明，MDIA-1，Forin同源结构域蛋白家族的成员和RhoGTP酶的效应器，以及ROCK-1信号通路在RAGE介导的心血管应激中所起的作用。在这项应用中，我们将探索RAGE在心脏中RAGE依赖的mdia-1和/或ROCK信号的完整背景下的作用。只有充分了解细胞特异性RAGE信号在心肌梗死中的潜在适应性作用，以及该受体在I/R中刺激的近端信号级联反应，才能实现RAGE拮抗的最佳设计。 公共卫生相关性：我们实验室的早期研究揭示了RAGE在心肌梗死中的关键作用，因为全局缺失RAGE导致减少心肌坏死，促进心脏功能恢复和保存能量代谢。这项拟议的研究将探索RAGE在心肌梗死后介导损伤的心脏中RAGE依赖的mdia-1和/或ROCK信号的完整背景下的作用。只有充分了解细胞特异性RAGE信号在心肌梗死中的潜在适应性作用，以及该受体在心肌梗死中刺激的近端信号级联反应，才能实现RAGE拮抗的最佳设计。

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.