Efferocytosis Directed Inflammation Resolution and Repair in the Hypoxic Heart

描述（由申请人提供）：心肌梗死（MI）后心力衰竭是发病率和死亡率的重要原因。虽然药理学的进步已经显著降低了死亡率，但MI后心力衰竭的剩余风险正在增加。这需要开发新的方法来保护心脏功能。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梗死面积，这是心肌细胞（CM）死亡的函数。通过吞噬作用有效地吞噬去除垂死的CM对于开始解决炎症和促进心脏修复至关重要。重要的是，死亡CM的吞噬清除率降低与MI后发病率和死亡率增加直接相关。最近的研究表明，单核细胞亚群是不同的负责吞噬和修复功能的心脏。在细胞水平之外，心肌吞噬细胞内的分子途径仍然未知，这是心脏中巨噬细胞介导的炎症消退所必需的。我的实验室已经发现，失活的红细胞信号通路恶化心肌梗死后的心脏修复，铺平了道路，为新的一类新的分子靶点，以促进伤口愈合的心脏。我们的研究表明，抑制CM“不要吃我”配体增强吞噬细胞的吞噬，并且凋亡细胞受体MERTK是CM吞噬作用所需的。我们在非基因靶向小鼠和人类中的数据表明，MERTK在MI期间通过蛋白水解和缺氧诱导因子（HIF）自然失活，重要的是，鼠MERTK缺陷会增加MI后的不良心肌心室重塑并促进心力衰竭。这些数据暗示凋亡细胞受体和CM不吃我配体作为MI后缺陷性红细胞增多症的候选者。这些初步结果导致了几个新的研究方向，这是本提案的重点，包括（I）MERTK依赖性红细胞增多和蛋白水解在风险因素如高脂血症和临床相关再灌注的背景下驱动MI后修复程度的程度，（II）缺氧期间MERTK依赖性和独立的红细胞增多和炎症消退机制，和（III）新的CM与MΦ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.