Targeting Macrophage Lysosome Biogenesis Program in Cardiomyopathy and Heart Failure

在美国，由心肌梗死（MI）引起的心力衰竭是导致死亡的主要原因。浸润 外周血单核细胞和驻留的心脏巨噬细胞被假定在心肌梗死后的 期，其特征在于早期阶段的促炎信号传导和死亡细胞的吞噬清除 以及向抗炎信号传导的转变以促进修复阶段。持续性促炎 巨噬细胞与适应不良的左心室重构和进行性心力衰竭相关。肥胖和 由此产生的（II型）糖尿病已达到流行病的比例，并易于发生心力衰竭 通过引起心肌中脂质过载的发展，即心脏脂毒性;以及通过促进冠状动脉 动脉疾病与其他风险因素如高血压、高脂血症和久坐不动的生活方式有关。 早期巨噬细胞募集驱动炎症并促进脂毒性心肌病的发展， 动物模型这些观察结果表明，调节巨噬细胞炎症表型的策略 可能具有治疗益处。新出现的数据指出，巨噬细胞中溶酶体功能的关键作用 炎症反应。TFEB和TFE 3，两个密切相关的家族成员已被证明是 作为巨噬细胞中溶酶体生物发生程序的主要转录激活因子， TFEB和TFE 3的激活对于维持巨噬细胞的存活是必需的 吞噬作用我们的初步和发表的研究结果表明，巨噬细胞TFEB表达 减弱心肌梗死后重塑并防止脂毒性细胞死亡。我们先前发现， 间歇性禁食激活TFEB以刺激心肌中的溶酶体功能，并减弱心脏功能。 心肌梗死时心肌细胞死亡。我们的初步数据表明，间歇性禁食可以挽救死亡率， 减弱炎症反应，以预防MHC-ACSL 1小鼠的心肌病和心力衰竭， 由于酰基辅酶A合成酶1（ACSL 1）的转基因表达引起的心脏脂毒性;这表明间歇性 禁食也可以调节巨噬细胞溶酶体功能和炎症反应。在本提案中，我们 假设TFEB/TFE 3介导巨噬细胞溶酶体生物合成的转录调节 程序对于减轻心肌梗死后和脂毒性应激下心肌中的炎症反应至关重要; 并且可以在治疗上用于预防心力衰竭。在目标1中，我们将研究 巨噬细胞溶酶体生物合成程序在预防心肌梗死后心力衰竭中的作用 MHC-ACS中心肌缺血-再灌注损伤和减轻继发于脂毒性的心肌病 小鼠模型在目的2中，我们将研究TFEB/TFE 3介导的巨噬细胞调节的机制， 表型。在目标3中，我们将评估海藻糖的功效，海藻糖是TFEB/TFE 3诱导的溶酶体的激活剂。 生物合成，在减轻巨噬细胞炎症反应和心肌病，心肌梗死后和下 脂毒应激这些研究将确定TFEB/TFE 3-转录程序作为潜在的治疗靶点 在心肌梗死后心力衰竭和脂毒性心肌病中调节心脏巨噬细胞功能。管理 海藻糖，一种天然存在的安全化合物，具有巨大的潜力，作为一种疗法，以激活这一点， 用于预防和/或治疗心肌病和心力衰竭的途径。

Heart failure due to myocardial infarction (MI) is leading cause of death in the United States. Infiltration of peripheral monocytes and resident cardiac macrophages are postulated to play a dual role in the post-MI period, characterized by pro-inflammatory signaling and phagocytic removal of dead cells in the early phase and a shift towards anti-inflammatory signaling to promote reparative phase. Persistence of pro-inflammatory macrophages correlates with maladaptive left ventricular remodeling and progressive heart failure. Obesity and resultant (type II) diabetes have reached epidemic proportions and predispose to development of heart failure by provoking development of lipid overload in myocardium, i.e. cardiac lipotoxicity; and by promoting coronary artery disease in concert with other risk factors such as hypertension, hyperlipidemia and a sedentary lifestyle. Early macrophage recruitment drives inflammation and promotes development of lipotoxic cardiomyopathy in animal models. These observations indicate that strategies to modulate macrophage inflammatory phenotype may be of therapeutic benefit. Emerging data point to a critical role for lysosomal function in macrophage inflammatory responses. TFEB and TFE3, two closely related family members have been demonstrated to function as the master transcriptional activators of the lysosomal biogenesis program in macrophages, acting in a mutually redundant fashion; and activation of TFEB and TFE3 is essential for sustaining macrophage phagocytosis. Our preliminary and published findings demonstrate that macrophage TFEB expression attenuates post-MI remodeling and protects against lipotoxic cell death. We have previously found that intermittent fasting activates TFEB to stimulate lysosome function in the myocardium and attenuate cardiac myocyte death during MI. Our preliminary data demonstrate that intermittent fasting rescues mortality and attenuates the inflammatory response to prevent cardiomyopathy and heart failure in MHC-ACSL1 mice with cardiac lipotoxicity due to transgenic expression of acylCoA-synthetase 1 (ACSL1); suggesting that intermittent fasting may also modulate macrophage lysosome function and the inflammatory response. In this proposal, we hypothesize that TFEB/TFE3-mediated transcriptional regulation of the macrophage lysosome biogenesis program is critical to attenuate inflammatory responses in the myocardium, post-MI and under lipotoxic stress; and can be harnessed therapeutically to prevent heart failure. In aim 1, we will examine the role of the macrophage lysosome biogenesis program in preventing post-MI heart failure in a closed chest model of cardiac ischemia-reperfusion injury and attenuating cardiomyopathy secondary to lipotoxicity in the MHC-ACS mouse model. In aim 2, we will examine the mechanisms for TFEB/TFE3-mediated modulation of macrophage phenotype. In aim 3, we will evaluate the efficacy of trehalose, an activator of TFEB/TFE3-induced lysosomal biogenesis, in attenuating the macrophage inflammatory response and cardiomyopathy, post-MI and under lipotoxic stress. These studies will identify TFEB/TFE3-transcriptional program as a potential therapeutic target to modulate cardiac macrophage function in post-MI heart failure and lipotoxic cardiomyopathy. Administration of trehalose, a naturally occurring and safe compound, has tremendous potential as a therapy to activate this pathway for prevention and/or treatment of cardiomyopathy and heart failure.