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Necessity of AMPK Activation for Caloric Restriction-Induced Cardioprotection

AMPK 激活对于热量限制诱导的心脏保护的必要性

基本信息

批准号：
8689461
负责人：
Qiangrong Liang
金额：
$ 43.17万
依托单位：
NEW YORK INST OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-05 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8689461
关键词：
5&apos -AMP-activated protein kinase Affect Aging Animals Apoptosis Attenuated Autophagocytosis Caloric Restriction Cardiac Cardiac Myocytes Cardiovascular system Dietary Intervention Dominant-Negative Mutation Eating Environment Functional disorder Glucose Goals Grant Growth Health Heart Heart Diseases Homeostasis Injury Institution Intake Knock-out Lead Learning Longevity Lower Organism Measures Mediating Metabolic Pathway Mitochondria Modeling Molecular Morphology Mus Mutant Strains Mice Myocardial Oxidative Stress Pharmaceutical Preparations Preventive Preventive Intervention Process Quality Control Regimen Reporter Research Research Activity Resistance Risk Factors Rodent Role Serum Signal Pathway Signal Transduction Simulate Structure Students Testing Therapeutic Therapeutic Intervention Transgenic Mice cardiovascular disorder risk constriction design endoplasmic reticulum stress feeding food consumption improved insight mTOR protein mimetics novel pressure public health relevance response sensor

项目摘要

Project Summary Excessive calorie intake poses an increased risk for cardiovascular disease. By contrast, caloric restriction (CR) can enhance cardiovascular health. Indeed, CR not only reduces several risk factors for heart disease, but also directly affects cardiac growth and function. These observations demonstrate a preventive and therapeutic potential of CR for heart disease. Recent research has focused on developing drugs that mimic CR's health-promoting effects without reducing food intake. However, the mechanisms of cardioprotection by CR remain speculative, making it hard to design mimetics for harnessing the full benefits of CR. Therefore, our long-term goal is to identity the underlying mechanisms responsible for CR-induced cardioprotection. AMP- activated protein kinase (AMPK) is an energy sensor that regulates multiple metabolic pathways to maintain cellular energy homeostasis. AMPK has been implicated in CR-induced longevity in lower organisms and in CR-conferred resistance to cardiac injury in rodents. However, the specific role of AMPK in CR-induced cardioprotection has never been definitively confirmed. It is also unclear whether and how AMPK engages its downstream effectors to exert the cardioprotective effects in response to CR. We showed that CR dramatically improved cardiac function and attenuated pressure overload-induced pathological cardiac remodeling. The cardioprotective effect of CR was accompanied by the activation of AMPK and the corresponding alteration of its potential downstream effectors. These results not only demonstrate the ability of CR to protect the heart in the setting of pressure overload, but also lead us to hypothesize that the activation of AMPK signaling pathway is essential for CR to maintain cardiac homeostasis at baseline and to antagonize pathological cardiac remodeling in response to pressure overload. This hypothesis will be tested in two specific aims. Using AMPK deficient mice including knockout and dominant negative transgenic mice, Aim1 will examine whether AMPK activation is required for CR to provide cardioprotection under both baseline and pressure overload conditions. Using both animal and cardiomyocyte culture models, Aim 2 will explore the mechanisms by which AMPK mediates the cardioprotective effects of CR. We will examine whether AMPK functions upstream of the mammalian target of rapamycin and autophagy to enhance mitochondrial quality control and promote myocardial survival. We have constructed a novel reporter that will allow direct quantification of the mitochondria that are being degraded through the mitophagic process in cultured cardiomyocytes. Successful completion of the proposed study will provide novel insights into the signaling mechanisms that mediate the cardioprotective effects of CR and facilitate the targeted design of effective mimetics to harness the power of CR for preventive and therapeutic intervention of heart disease.

项目摘要热量摄入过多会增加患心血管疾病的风险。相比之下， (CR)可以增强心血管健康。事实上，CR不仅减少了心脏病的几个风险因素，而且直接影响心脏的生长和功能。这些观察结果表明， CR对心脏病的治疗潜力。最近的研究集中在开发药物， CR的健康促进作用，而不减少食物的摄入量。然而，心脏保护的机制， CR仍然是推测性的，因此很难设计模拟物来充分利用CR的好处。所以我们的长期目标是确定CR诱导的心脏保护的潜在机制。AMP- 活化蛋白激酶（AMPK）是一种能量传感器，它调节多种代谢途径，以维持细胞能量平衡AMPK与低等生物中CR诱导的寿命有关， CR-赋予啮齿类动物对心脏损伤的抵抗力。然而，AMPK在CR-induced 心脏保护从未得到明确证实。目前还不清楚AMPK是否以及如何参与其下游效应物以响应CR发挥心脏保护作用。我们发现CR 改善心脏功能和减弱压力超负荷诱导的病理性心脏重塑。的 CR的心脏保护作用伴随着AMPK的激活和相应的其潜在的下游效应器。这些结果不仅证明了CR在治疗中保护心脏的能力，压力超负荷的设置，也使我们假设AMPK信号通路的激活对于CR维持基线时的心脏内稳态和对抗病理性心脏收缩是必需的。压力超负荷导致的重塑。这一假设将在两个具体目标中得到检验。使用AMPK 缺陷小鼠包括基因敲除和显性阴性转基因小鼠，Aim 1将检查AMPK是否 CR需要激活以在基线和压力超负荷条件下提供心脏保护。 Aim 2将使用动物和心肌细胞培养模型，探索AMPK 介导CR的心脏保护作用。我们将研究AMPK是否在哺乳动物雷帕霉素和自噬的靶点，以增强线粒体质量控制和促进心肌存活率我们已经构建了一种新的报告，将允许直接量化的在培养的心肌细胞中通过线粒体吞噬过程被降解的线粒体。成功完成拟议的研究将提供新的见解信号机制，介导的 CR的心脏保护作用，并促进有效模拟物的有针对性的设计，以利用 CR用于心脏病的预防和治疗干预。