Treating secondary cardiomyopathies by mimicking the adaptive hepatic glucose fasting response

通过模仿适应性肝葡萄糖空腹反应来治疗继发性心肌病

• 批准号: 10170418
• 负责人: Brian Jesse DeBosch
• 金额: $ 67.82万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10170418
• 关键词: Attenuated; Autophagocytosis; Caloric Restriction; Cardiac; Cardiac Myocytes; Cardiometabolic Disease; Cardiomyopathies; Cardiovascular system; Catabolism; Chronic; Clinical; Clinical Trials; Data; Disaccharides; Disease; Disease model; FGF21 gene; Fasting; Fatty Liver; Functional disorder; Gene Expression; Glucose Transporter; Goals; Growth; Growth Factor Receptors; Heart Diseases; Heart failure; Hepatic; Hepatocyte; Human; Hypertrophy; Infarction; Insulin Resistance; Intermittent fasting; Ischemia; Laboratories; Left Ventricular Hypertrophy; Light; Liver; Metabolism; Modeling; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardium; Nutraceutical; Oral; Pathologic; Pathway interactions; Patients; Pharmacology; Publishing; Reagent; Receptor Signaling; Reperfusion Injury; Reperfusion Therapy; Resistance; Rodent; Secondary Myocardial Diseases; Signal Transduction; Stimulus; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Trehalase; Trehalose; Work; analog; cardioprotection; cardiovascular risk factor; clinically relevant; constriction; efficacy evaluation; fasting glucose; genetic approach; glucose metabolism; glucose transport; improved; inhibitor/antagonist; innovation; microbial; mimetics; mortality; mouse genetics; mouse model; next generation; novel; novel therapeutics; peptide hormone; pressure; prevent; response; small molecule; tool

ABSTRACT Intermittent fasting and caloric restriction are newly identified therapeutic interventions against cardiometabolic disease. Our laboratory discovered that activating the hepatic glucose fasting response is sufficient to convey several of the key therapeutic effects of generalized caloric restriction. This is clinically relevant because targeting hepatic glucose transport is highly amenable to small-molecule and nutraceutical therapy. Therefore, our long-term goal is to understand adaptive liver glucose metabolism during fasting to produce new therapies that leverage these pathways against cardiometabolic disease. Intermittent fasting in rodents blocks pathological remodeling and infarct expansion after myocardial infarction, and treating mice with FGF21 – a liver-derived peptide hormone secreted in response to fasting – prevents experimental cardiac left ventricular hypertrophy (LVH) and LV dysfunction. We demonstrated that blocking hepatic glucose transport using the naturally occurring disaccharide, trehalose, recapitulates the hepatic adaptive fasting response. Our new data now demonstrate that oral trehalose recapitulates the effects of intermittent fasting on cardiac protection against pathological remodeling. Specifically, trehalose induces hepatic FGF21, and prevents pathological LVH and LV dysfunction in response to chronic pressure overload. We also identified a novel trehalose analog that resists degradation by host and microbial metabolism, and which activates hepatic fasting-like signal transduction to a greater extent than native trehalose. This study’s objective is thus to define mechanisms and contexts of cardioprotection by trehalose-class compounds as a prelude to the use of these compounds in human trials. Our central hypothesis is that hepatic GLUT inhibition blocks LVH and LVD by activating canonical hepatic fasting signals to the myocardium. We propose three Specific Aims to test this hypothesis. In Aim 1, we will delineate mechanisms by which trehalose prevents LVH and LVD. In Aim 2, we define pathophysiological contexts in which trehalose attenuates secondary cardiomyopathies. In Aim 3, we examine the impact of trehalose catabolism on its efficacy against secondary cardiomyopathies. The innovation of this proposal is that we our team has identified and will examine further: 1) a novel and tractable cardioprotective pathway, and 2) a novel compound class that activates this cardioprotective pathway. Completing these aims will define how hepatocyte fasting responses protect from pathological remodeling and dysfunction; and nominate specific clinical contexts in which the adaptive hepatic fasting response is cardioprotective. The impact of this work is that it will mechanistically inform next-generation glucose fasting- mimetics, which also leverage the adaptive fasting response against cardiac disease, and will justify further efforts toward clinical trials that utilize trehalose-class compounds to ameliorate secondary cardiomyopathies.

摘要 间歇性禁食和热量限制是新近发现的针对心脏代谢的治疗干预措施 疾病。我们的实验室发现，激活肝脏葡萄糖的空腹反应足以传递 普遍热量限制的几个关键治疗效果。这在临床上是相关的，因为 靶向肝脏葡萄糖转运对小分子药物和营养疗法是非常有利的。因此， 我们的长期目标是了解禁食期间的适应性肝脏葡萄糖代谢，以产生新的治疗方法。 利用这些途径对抗心脏代谢性疾病。 啮齿动物的间歇性禁食阻止了心肌梗死后的病理重构和梗塞扩大， 用FGF21-一种因禁食而分泌的肝源性多肽荷尔蒙-治疗小鼠，可以防止 实验性心脏左室肥厚(LVH)和左心功能不全。我们演示了阻止 利用自然产生的双糖--海藻糖--转运肝脏的葡萄糖 适应性禁食反应。我们的新数据现在表明，口服海藻糖概括了 间歇性禁食对心脏病理重构的保护作用。具体地说，海藻糖能诱导肝脏 FGF21，并预防慢性压力超负荷所致的病理性LVH和LV功能障碍。我们也 确定了一种新的海藻糖类似物，它可以抵抗宿主和微生物代谢的降解，并且 比天然海藻糖在更大程度上激活肝脏禁食样信号转导。这项研究的目的 因此定义了海藻糖类化合物的心脏保护机制和背景，作为 这些化合物在人体试验中的使用。我们的中心假设是肝脏过剩抑制阻断了左心室肥厚 和LVD，通过激活规范的肝脏禁食信号到心肌。 我们提出了三个具体目标来检验这一假设。在目标1中，我们将描述通过哪些机制 海藻糖可预防LVH和LVD。在目标2中，我们定义了海藻糖衰减的病理生理环境 继发性心肌病。在目标3中，我们研究了海藻糖分解代谢对其抗肿瘤疗效的影响。 继发性心肌病。 这一建议的创新之处在于，我们和我们的团队已经确定并将进一步研究：1)一种新颖的 易处理的心脏保护途径，和2)一种新的化合物类，激活这一心脏保护途径。 完成这些目标将定义肝细胞禁食反应如何保护免受病理性重构和 功能障碍；并指定适应性肝脏空腹反应是 保护心脏。这项工作的影响是，它将机械地通知下一代葡萄糖禁食- 模拟，这也利用了心脏疾病的适应性禁食反应，并将进一步证明 利用海藻糖类化合物改善继发性心肌病的临床试验的努力。