Novel mechanism mediating cardiac protection upon pressure overload

摘要 压力超负荷引起的心肌肥厚，例如由慢性高血压引起的心肌肥厚，是一个关键的风险。 导致心力衰竭的因素。从对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厚不是代偿性的，而是一种 不适应的过程。因此，对病理性心肌肥厚的调控日益被认为是一种 在预防心力衰竭的发展方面有潜在的前景。尽管进行了密集的研究 经过几十年的努力，肥厚性心力衰竭的分子机制尚不完全清楚。 我们最近的研究发现，含有Valosin的蛋白(VCP)，一种以前未被表征的蛋白质 在心脏中，代表心脏保护的介体，与心脏状况直接相关 高血压患者的肥大和功能障碍。这项建议的独创性是基于 我们的初步研究发现，在压力超负荷的心脏，VCP的表达显著下调 在各种动物模型中。我们还发现，在转基因小鼠中心脏特异的VCP过表达 显著减轻压力超负荷所致的心肌肥大和功能障碍 VCP在压力超负荷的情况下会加速心功能障碍，也会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具有双重调节作用 (MTOR)在心里。在初步数据的支持下，我们的总体假设是VCP是一种新颖的 保护心脏免受压力超负荷引起的心肌肥大和功能障碍的介体 选择性激活mTORC2但抑制mTORC2对心肌细胞存活和生长的调节 心脏应激状态下的mTORC1信号转导。因此，在这个建议中，我们将进一步阐明生理上的 基础状态和压力超负荷状态下心脏VCP的相关性和潜在机制 通过两个具体目标。我们的第一个目标是确定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 血管紧张素转换酶缺乏是衰老过程中心肌肥大和功能障碍的发病机制 在心脏压力超负荷的情况下，VCP的过度表达将提供对心脏的保护 在这种情况下恶化。我们的第二个目标是阐明心脏病的分子机制。 由VCP提供的保护。我们将测试我们的假设，即VCP作为mTOR的独特双重调节器 选择性激活存活复合体mTORC2但抑制促生长复合体 病理性应激条件下的mTORC 1。我们还假设，VCP的这种选择作用取决于它的 N-末端调节结构域。基于我们广泛的初步数据和之前的出版物，我们强烈 相信我们提出的使用体内、体外和体外综合方法的研究将 阐明VCP在压力超负荷下保护心脏的具体机制 将为防治心力衰竭提供新的策略。 。

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. .