Efferocytosis Directed Inflammation Resolution and Repair in the Hypoxic Heart

描述(由申请人提供)：心肌梗塞(MI)后的心力衰竭是发病率和死亡率的重要原因。尽管药物方面的进步显著降低了死亡率，但心肌梗塞后心力衰竭的残余风险正在增加。这就需要开发新的方法来保护心脏功能。急性心肌梗死急性期的组织损伤程度是导致心脏功能受损的后续不良重塑程度的关键决定因素。因此，一个重要的目标是最小化心肌梗死面积，这是心肌细胞(CM)死亡的一个功能。通过吞噬作用有效地吞噬掉濒临死亡的CMS，对于启动消炎和促进心脏修复至关重要。重要的是，死亡CMS的吞噬清除减少与MI后发病率和死亡率的增加直接相关。最近的研究表明，单核细胞亚群对心脏的吞噬和修复功能起着不同的作用。在细胞水平之外，心肌吞噬细胞内的分子通路仍不清楚，这是通过吞噬作用导致心脏炎症消退所必需的。我的实验室发现，泡泡吞噬信号通路的失活会恶化心肌梗死后的心脏修复，为新的一类促进心脏伤口愈合的分子靶点铺平道路。我们的研究表明，抑制CM“Do‘t Eat Me”配基可以增强吞噬细胞的吞噬作用，而凋亡细胞受体MERTK是CM泡腾所必需的。我们在非基因靶向的小鼠和人类中的数据表明，MERTK在心肌梗死期间被蛋白质分解和低氧诱导因子(HIF)自然失活，重要的是，小鼠MERTK缺乏会增加不利的心肌重构，并促进心肌梗死后的心力衰竭。这些数据表明，细胞凋亡受体和CM不吃我的配体是心肌梗塞后有缺陷的泡沫症的候选者。这些初步结果导致了几个新的研究方向，这些都是本提案的重点，包括(I)在高脂血症和临床相关再灌注等危险因素的背景下，MERTK依赖的胞吐和蛋白分解在多大程度上推动了MI后修复的程度，(Ii)MERTK依赖的独立的缺氧时泡出和炎症消退的机制，以及(Iii)CM与MΦS的新的相互作用。

DESCRIPTION (provided by applicant): Heart failure after myocardial infarction (MI) is a significant cause of morbidity and mortality. Though pharmacological advances have significantly reduced mortality, the residual risk of post MI-induced heart failure is increasing. This necessitates development of new approaches to preserve heart function. The extent of tissue damage in the acute phase of MI is a critical determinant of the degree of subsequent adverse remodeling that leads to impaired cardiac performance. As such, an important goal is to minimize infarct size, which is a function of cardiomyocyte (CM) death. Efficient phagocytic removal of dying CMs by efferocytosis is critical to initiating resolving inflammation and promoting heart repair. Importantly, reduced phagocytic clearance of dying CMs is directly correlated with increased morbidity and mortality post MI. Recent studies have shown monocyte subsets to be differentially responsible for phagocytic and repair functions in the heart. Beyond the cellular level, the molecular pathways within myocardial phagocytes, required for efferocytosis- directed inflammation resolution in the heart, remain unknown. My laboratory has made the discovery that inactivation of efferocytosis signaling pathways worsen heart repair after MI, paving the way for new a new class of molecular targets to promote wound healing in the heart. Our studies show that suppression of CM "don't eat me" ligands enhance engulfment by phagocytes, and that the apoptotic cell receptor MERTK, is required for CM efferocytosis. Our data in non-gene targeted mice and humans indicate MERTK is naturally inactivated during MI by proteolysis and hypoxia inducible factors (HIFs) and importantly, murine MERTK deficiency increases adverse myocardial ventricular remodeling and promotes heart failure after MI. These data implicate apoptotic cell receptors and CM don't-eat-me ligands as candidates for defective efferocytosis post MI. These initial results led to several new lines of investigation, which are the focus of this proposal, including (I) the degree to which MERTK-dependent efferocytosis and proteolysis drives the extent of post MI repair in the setting of risk factors suh as hyperlipidemia and clinically-relevant reperfusion, (II) MERTK- dependent and independent mechanisms of efferocytosis and inflammation resolution during hypoxia, and (III) novel CM interactions with MΦs.