Metabolic Regulation in Heart Failure

我们的长期目标是确定心力衰竭期间线粒体缺陷的机制，并 针对这些缺陷设计基于机制的治疗，作为治疗心脏的新方法 失败了。现在有令人信服的证据表明，在两种动物模型中都存在电子传输链异常。 和人类心力衰竭，但这些缺陷的分子基础及其在心力衰竭病理生理学中的作用 心力衰竭仍不清楚。有丝分裂形态异常，以及I、III、IV和V复合体 无论是在特定的心力衰竭动物模型中还是在人类中，电子传输链都被报道过 来自心力衰竭患者的心脏。因此，虽然通过氧化磷酸化损害了ATP的产生 可能是心脏衰竭的一个共同主题，具体的异常可能取决于心脏 研究心力衰竭模型，或患者心力衰竭的病因。这项提案旨在测试 假设微栓子导致的心力衰竭模型与心磷脂的损害有关， 这限制了复杂的IV活动，从而限制了心肌ATP的可用性，而起搏导致的心力衰竭 模型导致了复合体III中的一个缺陷，这再次限制了ATP的可用性。一个相关的问题是， 线粒体ETC缺陷和伴随的能量缺陷参与了糖尿病的病理生理过程。 心力衰竭的进展或代表心力衰竭引起的继发性变化。了解 线粒体等缺陷的分子基础和机制将提供一个框架来设计和 开发以机制为基础的干预措施，解决线粒体参与的首要问题。特定的 目的1是测量氧化磷酸化的速率和电子传输链的活性 对照犬心脏肌膜下和纤维间区线粒体复合体的研究 在从早期充血性心力衰竭发展到晚期充血性心力衰竭的心力衰竭过程中，在目标2中， 微栓塞症模型中线粒体复合体IV的缺陷将通过确定 动力学、络合物IV的量、亚基组成、细胞色素含量和脂质环境， 尤其是心磷脂。具体目标3将是确定复合体中缺陷的位置！11在起搏中- 通过确定部分反应、成分和脂质环境来诱导模型。在AIM 4 线粒体氧化磷酸化和电子传输链活性将作为 两种心力衰竭模型的治疗试验。AIM 5将测量氧化磷酸化和 微栓塞犬骨骼肌线粒体电子传输链活性的研究 起搏诱导的心力衰竭以确定骨骼肌线粒体功能是否受到影响 两种动物模型。这些研究强烈表明，体液因素(S)可能会影响骨骼 两种模型的肌肉线粒体代谢。

Our long term goal is to define the mechanism for the mitochondrial defects during heart failure and to devise mechanism-based therapies towards these defects as new approaches to the treatment of heart failure. There is now compelling evidence of electron transport chain abnormalities in both animal models and human heart failure, but the molecular bases for these defects and their role in the pathophysiology of heart failure remain unclear. Abnormalities in mitoch0ndrial morphology, and in complexes I, III, IV and V of the electron transport chain have all been reported in either specific animal models of heart failure or human hearts from patients with heart failure. Thus, while impaired ATP production via oxidative phosphorylation may be a common theme in the failing heart, the specific abnormalities may be dependent on the heart failure model studied, or the etiology of the heart failure in patients. This proposal is designed to test the hypothesis that the microembolism-induced heart failure model is associated with damage to cardiolipin, which limits complex IV activity, and thus myocardial ATP availability, while the pacing-induced heart failure model induces a defect in complex III, which again limits ATP availability. A relevant issue is whether the mitochondrial ETC defects and accompanying energy deficits are involved in the pathophysiology of progression of heart failure or represent secondary changes resulting from heart failure. Understanding the molecular basis and mechanisms for the mitochondrial ETC defects will provide a framework to devise and develop mechanism-based interventions that address the primacy of mitochondrial involvement. Specific aim 1 is to measure the rate of oxidative phosphorylation and the activity of the electron transport chain complexes in mitochondria isolated from the subsarcolemmal and the interfibrillar area of control dog heart and during heart failure during progression from early to advanced congestive heart failure, in aim 2 the site of defect in the mitochondrial complex IV in the microembolism model will be examined by determining kinetics, the amount of complex IV, the subunit composition, cytochrome content, and the lipid environment, especially cardiolipin. Specific aim 3 will be to determine the site of defect in complex !11in the pacing- induced model by determining partial reactions, components, and the lipid environment. In aim 4 mitochondrial oxidative phosphorylation and electron transport chain activity will be used as an endpoint in the therapeutic trials with both models of heart failure. Aim 5 will measure oxidative phosphorylation and electron transport chain activities in skeletal muscle mitochondria isolated from dogs with microembolisation- and pacing-induced heart failure to determine whether skeletal muscle mitochondrial function is affected in both animal models. These studies would strongly suggest that a humoral factor(s) may affect skeletal muscle mitochondrial metabolism in both models.