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: 10265358
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265358
• 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; efficacy evaluation; gain of function; inflammatory marker; loss of function; macrophage; military veteran; 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.

由于心肌梗塞（MI）引起的心力衰竭是美国死亡的主要原因。渗透 假定外围单核细胞和常驻心脏巨噬细胞在MI后起双重作用 时期，其特征是促炎的信号传导和死细胞的吞噬细胞去除 并转向抗炎信号传导以促进修复阶段。促炎的持久性 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 导致的（II型）糖尿病已经达到了流行比例，并且倾向于发展心力衰竭 通过挑衅心肌中脂质超负荷的发展，即心脏脂肪毒性；并通过提升冠状动脉 与其他危险因素一致的动脉疾病，例如高血压，高脂血症和久坐的生活方式。 早期巨噬细胞招募驱动炎症并促进脂肪毒性心肌病的发展 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。新兴数据表明巨噬细胞中溶酶体功能的关键作用 炎症反应。 TFEB和TFE3，已经证明了两个密切相关的家庭成员 充当巨噬细胞中溶酶体生物发生程序的主转录激活剂，作用 以相互多余的方式； 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发现表明巨噬细胞TFEB表达 减弱MI后重塑并预防脂肪毒性细胞死亡。我们以前发现 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 Mi期间的心肌病毒。我们的初步数据表明，间歇性禁食挽救死亡率和 减轻炎症反应以防止MHC-ACSL1小鼠的心肌病和心力衰竭 由于酰基Coa联合促酶1的转基因表达引起的心脏脂毒性（ACSL1）；暗示间歇性 禁食也可能调节巨噬细胞溶酶体功能和炎症反应。在这个建议中，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 程序对于减轻心肌，MI后和脂肪毒性应激的炎症反应至关重要。 并且可以治疗以防止心力衰竭。在AIM 1中，我们将研究 巨噬细胞溶酶体生物发生计划，以防止在封闭的胸部模型中进行MI后心力衰竭 MHC-ACS中脂肪毒性继发于脂肪毒性的心脏缺血 - 再灌注损伤和衰减心肌病 鼠标模型。在AIM 2中，我们将检查TFEB/TFE3介导的巨噬细胞调节的机制 表型。在AIM 3中，我们将评估TFEB/TFE3诱导的溶酶体激活剂Trehalose的功效 生物发生，在减弱巨噬细胞炎症反应和心肌病时，MI之后 脂肪毒性应激。这些研究将确定TFEB/TFE3转录程序是潜在的治疗靶点 在MI后心力衰竭和脂肪毒性心肌病中调节心脏巨噬细胞功能。行政 海藻糖是一种天然存在且安全的化合物，具有巨大的潜力作为激活此事的疗法 预防和/或治疗心肌病和心力衰竭的途径。

项目成果

More Energy to Relax: Targeting Epigenetic Effects of Acute Renal Injury to Prevent HFpEF.

• DOI: 10.1016/j.jacbts.2020.12.016
• 发表时间: 2021-03
• 期刊: JACC. Basic to translational science
• 作者: Diwan A

Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy.

• DOI: 10.1161/circulationaha.121.058411
• 发表时间: 2022-09-20
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Dhingra, Rimpy;Rabinovich-Nikitin, Inna;Rothman, Sonny;Guberman, Matthew;Gang, Hongying;Margulets, Victoria;Jassal, Davinder S.;Alagarsamy, Keshav N.;Dhingra, Sanjiv;Ripoll, Carla Valenzuela;Billia, Filio;Diwan, Abhinav;Javaheri, Ali;Kirshenbaum, Lorrie A.
• 通讯作者: Kirshenbaum, Lorrie A.

Chimeric Antigen Receptor Macrophages Target and Resorb Amyloid Plaques in a Mouse Model of Alzheimer's Disease.

嵌合抗原受体巨噬细胞在阿尔茨海默病小鼠模型中靶向并吸收淀粉样斑块。

• DOI: 10.1101/2023.04.28.538637
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Pan,Qiuyun;Yan,Ping;Kim,AlexanderB;Xiao,Qingli;Pandey,Gaurav;Haecker,Hans;Epelman,Slava;Diwan,Abhinav;Lee,Jin-Moo;DeSelm,CarlJ
• 通讯作者: DeSelm,CarlJ

Targeting the Autophagy-Lysosome Pathway in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure.

• DOI: 10.1016/j.jacbts.2022.06.003
• 发表时间: 2022-12
• 期刊: JACC-BASIC TO TRANSLATIONAL SCIENCE
• 影响因子: 9.7
• 作者: Evans, Sarah;Ma, Xiucui;Wang, Xiqiang;Chen, Yana;Zhao, Chen;Weinheimer, Carla J.;Kovacs, Attila;Finck, Brian;Diwan, Abhinav;Mann, Douglas L.
• 通讯作者: Mann, Douglas L.

Drugging the Hippo (Pathway): A Strategy to Stimulate Cardiac Regeneration?

• DOI: 10.1016/j.jacbts.2018.09.003
• 发表时间: 2018-10
• 期刊: JACC. Basic to translational science
• 作者: Mani K;Diwan A
• 通讯作者: Diwan A