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: 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
• 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

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. .

概括 压力超负荷引起的心脏肥大，例如由慢性高血压引起的，是关键风险 心力衰竭的因素。来自患者和动物模型研究的研究积累证据表明 慢性压力超负荷引起的心脏肥大不是补偿性，而是 适应不良的过程。因此，病理心肌肥大的调节越来越被认为是 预防心力衰竭发展的潜在有前途的方法。尽管进行了深入的研究 几十年来的努力，肥厚性心力衰竭的分子机制尚未完全理解。 我们最近的研究发现，含勇气蛋白的蛋白质（VCP），一种以前未表征的蛋白质 在心脏中，代表与心脏状况直接相关的心脏保护介质 患者高血压引起的肥大和功能障碍。该提议的独创性是基于 我们的初步发现，即在压力超负荷的心脏中VCP表达显着下调 在变异动物模型中。我们还发现转基因小鼠中VCP的心脏特异性过表达 大大削弱了压力超负荷引起的心脏肥大和功能障碍，而受损 VCP在压力超负荷下加速心脏功能障碍，并加快与年龄相关的心肌病。 我们还发现，VCP对雷帕霉素的机理靶标信号提出了双重调节作用 （mtor）心中。正如初步数据所支持的那样，我们的总体假设是VCP是一种新颖 保护心脏免受压力超负荷引起的心脏肥大和功能障碍的介体 通过选择性激活MTORC2，调节心肌细胞的存活和生长，但抑制 MTORC1在心脏应力下信号传导。因此，在此提案中，我们将进一步阐明生理 相关性和VCP心脏中VCP的潜在机制在基线和压力超负荷下 通过两个具体的目标。我们的第一个目的是确定VCP与心脏的生理相关性 衰老期间和压力超负荷的生长和功能。我们将检验我们的假设 VCP的不足是导致衰老期间心肥大和功能障碍的发病机理 在心脏的压力超负荷下，过表达的VCP将为心脏提供保护 在这些条件下恶化。我们的第二个目的是阐明心脏的分子机制 VCP授予的保护。我们将检验我们的假设，即VCP充当MTOR的独特双调节器 通过选择性激活生存络合物MTORC2，但抑制促进生长复合物来复合物 MTORC1在病理压力下。我们还假设VCP的这种选择性效应取决于其 N末端调节域。根据我们广泛的初步数据和以前的出版物，我们强烈 相信我们提出的使用综合体内，体内和体外方法的研究将 阐明VCP在压力超负荷下通过VCP涉及的特定机制 将提供一种防止和治疗心力衰竭的新策略。 。