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.

项目摘要过度的卡路里摄入量会增加心血管疾病的风险。相比之下，热量限制（CR）可以增强心血管健康。确实，CR不仅减少了心脏病的几个危险因素，但也直接影响心脏生长和功能。这些观察结果表明了一种预防性和 CR对于心脏病的治疗潜力。最近的研究重点是开发模仿的药物 CR的促进健康效果而不减少食物摄入量。但是，通过 CR保持投机性，因此很难设计模仿物来利用CR的全部好处。因此，我们的长期目标是识别负责CR诱导心脏保护的基本机制。放大器活化的蛋白激酶（AMPK）是一种能量传感器，可调节多种代谢途径以维持细胞能量稳态。 AMPK与CR诱导的较低生物和中的寿命有关啮齿动物中CR限制了对心脏损伤的抵抗力。但是，AMPK在CR诱导的特定作用心脏保护从未得到明确确认。还不清楚AMPK是否以及如何参与下游效应子以响应CR发挥心脏保护作用。我们表明Cr急剧改善心脏功能并减弱压力超负荷引起的病理心脏重塑。这 CR的心脏保护作用伴随着AMPK的激活和相应的改变它的潜在下游效应子。这些结果不仅证明了CR保护心脏的能力压力超负荷的设置，但也使我们假设AMPK信号通路的激活对于CR在基线时保持心脏体内平衡并与病理心脏拮抗是必不可少的响应压力超负荷的重塑。该假设将以两个具体的目的进行检验。使用AMPK 不足的小鼠包括基因敲除和主要的负转基因小鼠，AIM1将检查AMPK是否是否 CR在基线和压力超负荷条件下提供心脏保护需要激活。使用动物和心肌细胞培养模型，AIM 2将探索AMPK的机制介导Cr的心脏保护作用。我们将检查AMPK是否在上游雷帕霉素和自噬的哺乳动物靶标可增强线粒体质量控制并促进心肌生存。我们已经构建了一个新的记者，可以直接量化线粒体通过培养的心肌细胞的线粒体过程降解。成功的拟议研究的完成将提供有关介导的信号传导机制的新见解 CR的心脏保护作用，并促进有效模仿物的目标设计，以利用 CR用于心脏病的预防和治疗干预。