Targeting Macrophage Lysosome Biogenesis Program in Cardiomyopathy and Heart Failure

在美国，心肌梗死(MI)引起的心力衰竭是主要的死亡原因。渗入 外周单核细胞和驻留的心脏巨噬细胞被认为在心肌梗死后起双重作用 早期，以促炎症信号和吞噬死亡细胞为特征 以及转向抗炎信号以促进修复阶段。持续的促炎作用 巨噬细胞与适应性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)糖尿病已经达到流行的程度，并容易发展为心力衰竭。 通过刺激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 动脉疾病与其他危险因素，如高血压、高脂血症和久坐不动的生活方式相一致。 早期巨噬细胞募集推动炎症并促进脂中毒性心肌病的发展 动物模型。这些观察表明，调节巨噬细胞炎症表型的策略 可能对治疗有好处。新数据指出溶酶体功能在巨噬细胞中的关键作用 炎症反应。TFEB和TFE3，这两个密切相关的家庭成员已经被证明 在巨噬细胞中作为溶酶体生物发生程序的主转录激活剂，作用于 TFEB和TFE3的激活对于维持巨噬细胞是必不可少的 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 减轻心肌梗死后的重塑，防止脂毒性细胞死亡。我们之前已经发现， 间歇性禁食激活TFEB刺激心肌溶酶体功能减弱心脏 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和 减轻炎症反应，预防MHC-ACSL1小鼠心肌病和心力衰竭 乙酰辅酶A合成酶1(ACSL1)转基因表达所致的心脏脂毒性；提示间歇性 禁食还可能调节巨噬细胞溶酶体功能和炎症反应。在这项提案中，我们 假设TFEB/TFE3介导的巨噬细胞溶酶体生物发生的转录调控 程序对减轻心肌梗死后和脂毒应激下的炎症反应至关重要； 并可用于治疗预防心力衰竭。在目标1中，我们将研究 巨噬细胞溶酶体生物发生程序预防急性心肌梗死后心力衰竭 MHC-ACS心肌缺血再灌注损伤与减轻脂毒性继发心肌病 老鼠模型。在目标2中，我们将研究TFEB/TFE3介导的巨噬细胞调节机制 表型。在目标3中，我们将评估海藻糖，一种TFEB/TFE3诱导的溶酶体的激活剂的效果 在减轻心肌梗死后和心肌梗死后巨噬细胞炎症反应和心肌病的生物发生 脂毒应激。这些研究将确定TFEB/TFE3转录程序为潜在的治疗靶点 目的：调节心肌梗死后心力衰竭和脂中毒性心肌病患者的心肌巨噬细胞功能。行政管理 海藻糖，一种天然存在的安全化合物，作为一种激活这一活性的疗法具有巨大的潜力 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.