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: 10442453
• 负责人: Brian Jesse DeBosch
• 金额: $ 62.96万
• 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/10442453
• 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; 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发现的针对心脏代谢紊乱的治疗干预措施。 疾病我们的实验室发现，激活肝脏葡萄糖空腹反应足以传达 几个关键的治疗效果的全面热量限制。这是临床相关的，因为 靶向肝葡萄糖转运非常适合于小分子和营养药物治疗。因此，我们认为， 我们的长期目标是了解禁食期间肝脏葡萄糖代谢的适应性，以产生新的治疗方法。 利用这些途径对抗心脏代谢疾病。 啮齿类动物的间歇性禁食阻断了心肌梗死后的病理性重塑和梗死扩展， 用FGF 21治疗小鼠，FGF 21是一种在禁食时分泌的肝源性肽激素， 实验性心脏左室肥大（LVH）和左室功能障碍。我们证明了阻断 利用天然存在的二糖海藻糖的肝葡萄糖转运， 适应性禁食反应我们的新数据现在表明，口服海藻糖重现了 间歇性禁食对心脏病理性重塑的保护作用。具体而言，海藻糖诱导肝脏 FGF 21，并预防病理性LVH和LV功能障碍，以响应慢性压力超负荷。我们也 鉴定了一种新的海藻糖类似物，其抵抗宿主和微生物代谢的降解，并且 比天然海藻糖更大程度地激活肝禁食样信号转导。本研究的目的 因此，定义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应用我们的中心假设是肝脏GLUT抑制阻断LVH 和LVD通过激活到心肌的典型肝禁食信号。 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 海藻糖预防LVH和LVD。在目标2中，我们定义了海藻糖减弱 继发性心肌病在目标3中，我们研究了海藻糖催化剂对其抗肿瘤功效的影响。 继发性心肌病 本提案的创新之处在于，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）激活该心脏保护途径的新型化合物类。 完成这些目标将定义肝细胞禁食反应如何保护免于病理性重塑， 功能障碍;并指定适应性肝脏禁食反应的特定临床背景 心脏保护。这项工作的影响是，它将机械地告知下一代葡萄糖禁食- 模拟，这也利用适应性禁食反应对心脏病，并将证明进一步 致力于利用海藻糖类化合物改善继发性心肌病的临床试验。