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Novel mechanism mediating cardiac protection upon pressure overload

压力过载时介导心脏保护的新机制

基本信息

批准号：
9917072
负责人：
Hongyu Qiu
金额：
$ 38.65万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917072
关键词：
Aging Animal Model Arrhythmia Attenuated Cardiac Cardiac Myocytes Cardiomyopathies Chronic Complex Data Deterioration Development FRAP1 gene Family suidae Growth Heart Heart Hypertrophy Heart failure Hospitalization Hypertension Hypertrophy Impairment In Vitro Left ventricular structure Mediating Mediator of activation protein Molecular Myocardial Myocardial Infarction Myocardial dysfunction N Domain N-terminal Pathogenesis Pathologic Patients Physiological Prevention Process Proteins Publications Rattus Regulation Research Risk Factors Role Scheme Signal Transduction Stress Sudden Death Testing Therapeutic Tissues Transgenic Mice Variant Wild Type Mouse age related base cardiogenesis cardioprotection constriction hypertensive heart disease in vivo mortality mouse model normotensive novel novel therapeutics originality overexpression pressure prevent protein expression response valosin-containing protein

项目摘要

Summary Pressure overload induced cardiac hypertrophy, such as that caused by chronic hypertension, is a key risk factor for heart failure. Accumulating evidence from studies in patients and animal models suggests that cardiac hypertrophy induced by the chronic pressure overload is not a compensatory but rather is a maladaptive process. Thus, modulation of pathological myocardial hypertrophy is increasingly recognized as a potentially promising approach in the prevention of development of heart failure. Despite intensive research efforts over several decades, the molecular mechanisms of hypertrophic heart failure are not fully understood. Our recent study found that the valosin-containing protein (VCP), a protein which is previously uncharacterized in the heart, represents a mediator of cardioprotection that is directly relevant to the condition of cardiac hypertrophy and dysfunction induced by hypertension in patients. The originality of this proposal is based on our preliminary findings that VCP expression is significantly down-regulated in the pressure overloaded hearts in variant animal models. We also found that cardiac specific overexpression of VCP in a transgenic mouse significantly attenuates the pressure overload induced cardiac hypertrophy and dysfunction, while impaired VCP accelerates cardiac dysfunction under pressure overload and also hastens age related cardiomyopathy. We also found that VCP presents a dual regulatory effect on the signaling of mechanistic target of rapamycin (mTOR) in the heart. As supported by the Preliminary Data, our overall hypothesis is that VCP is a novel mediator that protects heart against the pressure overload-induced cardiac hypertrophy and dysfunction by regulating the survival and growth of cardiomyocytes through selectively activating mTORC2 but inhibiting mTORC1 signaling under cardiac stress. Thus, in this proposal, we will elucidate further the physiological relevance and the underlying mechanisms of VCP in the heart at baseline and under pressure overload through two Specific Aims. Our first Aim is to determine the physiological relevance of VCP to the cardiac growth and function during aging and under pressure overload. We will test our hypothesis that an insufficiency of VCP is responsible for the pathogenesis of cardiac hypertrophy and dysfunction during aging and under pressure overload of heart, and an overexpression VCP will provide protection against the cardiac deterioration under these conditions. Our second Aim is to elucidate the molecular mechanisms of cardiac protection conferred by VCP. We will test our hypothesis that VCP acts as a unique dual regulator for mTOR complexes by selectively activating the survival complex mTORC2 but inhibiting the growth-promoting complex mTORC1 under the pathological stress. We also hypothesize that this selective effect of VCP depends on its N-terminal regulatory domain. Based on our extensive preliminary data and previous publications, we strongly believe that our proposed studies using the comprehensive in vivo, ex vivo and in vitro approaches will elucidate the specific mechanisms involved in the cardiac protection by VCP under pressure overload which will provide a new strategy for preventing and treating the heart failure. .

总结