Endothelial Cell Respiration in Atherosclerotic Plaque Erosion

动脉粥样硬化斑块的内皮细胞反应 心脏病是美国和全世界的头号死因。冠状 动脉疾病是最常见的心脏病类型，是急性冠状动脉疾病的根本原因。 综合征，并占全球每年740万人死亡。几乎所有这些事件都源于 动脉粥样硬化斑块破裂或侵蚀。虽然对斑块破裂的认识有所提高， 近几十年来，人们对牙菌斑侵蚀及其潜在的 分子机制-尽管最近认识到它可能导致25%至60%的急性 冠状动脉综合征的发病率正在上升。牙菌斑侵蚀的定义是 内皮细胞（EC）在没有斑块破裂的情况下导致血栓形成。的 糜烂的病理生理学在很大程度上是未探索的;关于这个主题的少数研究集中在外在的 导致EC损失的因素。然而，大多数糜烂在临床上是无声的，这表明， 侵蚀区域通常愈合良好，足以防止急性冠状动脉综合征。特别是 斑块侵蚀修复的分子机制尚不清楚。我们的研究计划 将研究EC内在因素，这些因素可能会改变EC死亡的可能性， 脱屑，或将有助于修复，特别是在线粒体机制看 在这个环境中还没有被探索过。在血管生成过程中，线粒体呼吸和 代谢通过ATP产生以外的机制支持EC增殖和迁移。 我们假设EC呼吸是支持内皮稳态和促进内皮细胞增殖的必要条件。 在再内皮化和斑块侵蚀期间进行修复。利用分子和细胞的工具 生物学和小鼠遗传学，我们将评估：a）EC呼吸是否促进细胞 与侵蚀斑块的内皮修复相关的活性，并揭示潜在的分子 机制，B）EC呼吸是否支持动脉内稳态或促进再循环。 动脉剥脱后内皮化，以及c）EC呼吸是否抑制斑块 侵蚀或支持侵蚀斑块的再内皮化。我们的研究还将包括一个 创新的方法来研究三维内皮，包括评估 人类动脉粥样硬化斑块。该研究项目将为 斑块侵蚀病理生理学的新生领域，专注于线粒体和细胞代谢， 这可能为预防或治疗急性冠状动脉综合征开辟新的途径。

Endothelial Cell Respiration in Atherosclerotic Plaque Erosion Heart disease is the number one cause of death in the United States and worldwide. Coronary artery disease, the most common type of heart disease, is the root cause of acute coronary syndromes, and accounts for 7.4 million deaths per year globally. Nearly all these events stem from atherosclerotic plaque rupture or erosion. While knowledge of plaque rupture has improved in recent decades, comparatively little is known about plaque erosion and its underlying molecular mechanisms – despite recent recognition that it may cause from 25 to 60% of acute coronary syndromes and is increasing in incidence. Plaque erosion is defined by loss of endothelial cells (ECs) leading to thrombosis in the absence of plaque rupture. The pathophysiology of erosion is largely unexplored; the few studies on this topic focus on extrinsic factors that induce EC loss. However, most erosions are clinically silent, which suggests that eroded regions usually heal well enough to prevent an acute coronary syndrome. Notably, the molecular mechanisms underlying repair in plaque erosion are unknown. Our research proposal will study EC intrinsic factors that may change the likelihood that ECs will be lost to death or desquamation, or will contribute to repair, in particular, looking at mitochondrial mechanisms that are unexplored in this setting. During angiogenesis, mitochondrial respiration and metabolism support EC proliferation and migration by mechanisms other than ATP production. We hypothesize that EC respiration is required to support endothelial homeostasis and promote repair during re-endothelialization and plaque erosion. Using tools of molecular and cellular biology and mouse genetics, we will evaluate: a) whether EC respiration promotes cellular activities relevant for endothelial repair of eroded plaques, and unveil underlying molecular mechanisms, b) whether EC respiration supports arterial homeostasis or promotes re- endothelialization after arterial denudation, and c) whether EC respiration oposses plaque erosion or supports re-endothelialization of eroded plaques. Our studies will also incorporate an innovative method to study the endothelium in three-dimensions, and include the evaluation of human atherosclerotic plaques. This research project will bring a new perspective to the nascent field of plaque erosion pathophysiology, focused on mitochondria and cell metabolism, which may open new avenues to prevent or treat acute coronary syndrome.