Novel mechanism mediating cardiac protection upon pressure overload

压力过载时介导心脏保护的新机制

• 批准号: 9926309
• 负责人: Hongyu Qiu
• 金额: $ 38.24万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926309
• 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

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 压力超负荷引起的心脏肥大，如慢性高血压引起的心脏肥大，是一个关键风险 心力衰竭的因素。从患者和动物模型的研究中积累的证据表明， 慢性压力超负荷引起的心肌肥大不是代偿性的，而是一种 适应不良的过程因此，病理性心肌肥大的调节越来越被认为是一种治疗方法。 在预防心力衰竭的发展方面具有潜在前景的方法。尽管深入研究 经过几十年的努力，肥厚性心力衰竭的分子机制尚未完全了解。 我们最近的研究发现，含有缬氨素的蛋白质（VCP），一种以前未被表征的蛋白质， 在心脏中，代表心脏保护的介质，其与心脏的状况直接相关。 高血压患者的肥大和功能障碍。这项提案的独创性是基于 我们的初步发现，VCP的表达在压力超负荷的心脏中显著下调， 在不同的动物模型中。我们还发现转基因小鼠心脏特异性VCP过表达， 显著减弱压力超负荷诱导的心脏肥大和功能障碍， VCP在压力超负荷下加速心功能不全，也加速与年龄相关的心肌病。 我们还发现VCP对雷帕霉素的机制靶点信号转导具有双重调节作用 （mTOR）在心脏。正如初步数据所支持的那样，我们的总体假设是，VCP是一种新的 保护心脏免受压力超负荷诱导的心脏肥大和功能障碍的介质， 通过选择性激活mTORC2而抑制mTORC2，调节心肌细胞的存活和生长， mTORC1信号在心脏应激下的作用。因此，在本建议中，我们将进一步阐明生理学 基线和压力超负荷下心脏VCP的相关性和潜在机制 通过两个具体目标。我们的第一个目的是确定VCP与心脏的生理相关性。 在老化和压力超负荷下的生长和功能。我们将测试我们的假设， VCP不足是衰老过程中心脏肥大和功能障碍的发病机制 在心脏压力超负荷下，VCP过表达将提供对心脏的保护， 在这种情况下恶化。我们的第二个目的是阐明心肌梗死的分子机制， VCP提供的保护。我们将测试我们的假设，即VCP作为一个独特的双重调节mTOR 通过选择性激活存活复合物mTORC2但抑制促生长复合物 mTORC1在病理应激下的表达。我们还假设VCP的这种选择性作用取决于其 N-末端调节结构域。根据我们广泛的初步数据和以前的出版物，我们强烈认为， 我相信，我们提出的使用全面的体内、体外和离体方法的研究将 阐明压力超负荷下VCP保护心脏的具体机制， 将为心力衰竭的防治提供新的策略。 .