Targeting Macrophage Lysosome Biogenesis Program in Cardiomyopathy and Heart Failure

心肌病和心力衰竭中的靶向巨噬细胞溶酶体生物发生程序

• 批准号: 9898259
• 负责人: Abhinav Diwan
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898259
• 关键词: Ablation; Affect; Animal Model; Anti-Inflammatory Agents; Atherosclerosis; Attenuated; Autophagocytosis; Biogenesis; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cause of Death; Cell Death; Cells; Cessation of life; Chest; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Disease; Epidemic; Excision; Family member; Genetic Transcription; Growth; Heart; Heart failure; Hyperlipidemia; Hypertension; Incidence; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intermittent fasting; Left Ventricular Remodeling; Ligase; Lipids; Lysosomes; Mediating; Methods; Mitochondria; Modeling; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocarditis; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Peripheral; Phagocytes; Phagocytosis; Phase; Phenotype; Play; Population Group; Prevalence; Prevention; Publishing; Quality Control; Reperfusion Injury; Risk Factors; Role; Secondary Myocardial Diseases; Secondary to; Signal Transduction; Stress; TFE3 gene; Testing; Therapeutic; Transcription Coactivator; Transcriptional Regulation; Transgenic Organisms; Trehalose; United States; Veterans; age group; aging population; attenuation; base; cardiogenesis; chemokine receptor; diabetic cardiomyopathy; gain of function; inflammatory marker; loss of function; macrophage; monocyte; mortality; mouse model; myocardial infarct sizing; overexpression; prevent; programs; recruit; sedentary lifestyle; therapeutic target; translational approach; vascular inflammation

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.

心肌梗塞 (MI) 引起的心力衰竭是美国的主要原因。渗透 外周单核细胞和常驻心脏巨噬细胞被认为在心肌梗死后发挥双重作用 阶段，其特征是早期促炎症信号传导和吞噬细胞清除死亡细胞 以及转向抗炎信号传导以促进修复阶段。促炎剂的持续存在 巨噬细胞与适应不良的左心室重塑和进行性心力衰竭相关。肥胖和 由此产生的（II 型）糖尿病已达到流行程度并容易发展为心力衰竭 通过引发心肌脂质超负荷的发展，即心脏脂毒性；并通过促进冠状动脉 动脉疾病与其他危险因素如高血压、高脂血症和久坐的生活方式有关。 早期巨噬细胞募集会导致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。新数据表明溶酶体功能在巨噬细胞中发挥关键作用 炎症反应。 TFEB 和 TFE3 这两个密切相关的家族成员已被证明 作为巨噬细胞溶酶体生物发生程序的主要转录激活剂， 以相互冗余的方式； TFEB 和 TFE3 的激活对于维持巨噬细胞至关重要 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。我们之前发现 间歇性禁食激活 TFEB 刺激心肌溶酶体功能并减弱心肌 MI 期间心肌细胞死亡。我们的初步数据表明，间歇性禁食可以降低死亡率 减轻 MHC-ACSL1 小鼠的炎症反应，预防心肌病和心力衰竭 酰基辅酶 A 合成酶 1 (ACSL1) 的转基因表达导致心脏脂肪毒性；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。在这个提案中，我们 假设 TFEB/TFE3 介导的巨噬细胞溶酶体生物发生的转录调节 该计划对于减轻心肌梗死后和脂毒性应激下心肌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在闭胸模型中预防心肌梗死后心力衰竭 MHC-ACS 中脂毒性继发的心脏缺血再灌注损伤和减轻型心肌病 鼠标模型。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，我们将评估海藻糖的功效，海藻糖是 TFEB/TFE3 诱导的溶酶体的激活剂。 生物发生，减轻巨噬细胞炎症反应和心肌病，心肌梗死后和心肌梗死后 脂毒性应激。这些研究将确定 TFEB/TFE3 转录程序作为潜在的治疗靶点 调节心肌梗死后心力衰竭和脂毒性心肌病中的心脏巨噬细胞功能。行政 海藻糖是一种天然存在且安全的化合物，作为激活这种物质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。