Investigating the role of respiratory complex I in the transition from pressure-inducedhypertrophy to heart failure by xenogeneic expression of Ndi1

通过 Ndi1 的异种表达研究呼吸复合物 I 在从压力诱导的肥大到心力衰竭的转变中的作用

• 批准号: 521667638
• 负责人: Professor Dr. Torsten Doenst
• 金额: --
• 依托单位: Klinik für Herz- und Thoraxchirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/521667638?language=en
• 关键词: Investigating; role; respiratory; complex; transition

Chronically increased pressure load to the heart causes cardiac hypertrophy, which eventually leads to contractile dysfunction and heart failure. Underlying mechanisms for this transition are still a matter of debate. Mitochondrial dysfunction based upon defects in the electron transport chain (ETC) has been proposed as a key mechanism. We and others demonstrated impaired respiratory capacities, specifically related to complex I, preceding the onset of contractile dysfunction. Respiratory chain complexes are therefore an attractive treatment target. In an earlier study, we have demonstrated that bypassing a defective respiratory complex III by alternative oxidase (AOX) in mice with Gracile syndrome can prevent the development of a lethal cardiomyopathy. We here propose to use Ndi1, a single subunit NADH dehydrogenase of Saccharomyces cerevisiae, to bypass complex I in a rat model of hypertrophy and heart failure induced by transverse aortic constriction (TAC). We generated rats constitutively expressing Ndi1 specifically for this purpose. Notably, Ndi1 transfers electrons directly from NADH to ubiquinone in a non-protonmotive manner and thus decreases ETC efficiency. If oxygen and reducing equivalents are abundant, however, complexes III and IV can compensate for the loss of complex I activity. Using Ndi1, we thus expect to prevent the onset of contractile dysfunction upon pressure load induced by TAC. The proposed study therefore serves three purposes. (1) We will test an intensely debated cause of pressure-induced heart failure (i.e., a possible defect in complex I). (2) We may lay the foundations for a new therapeutic concept, i.e., a bypass of impaired respiratory complexes by alternative enzymes such as Ndi1. (3) We address an old but never proven paradigm, where a “critical heart mass” is thought to cause regional hypoxia due to increasing oxygen diffusion distances during the development of hypertrophy. Since Ndi1 activity requires abundance in oxygen, we may possibly find out whether regional hypoxia is involved in the process of heart failure development, because a lack of oxygen would not allow Ndi1 to elicit disease-mitigating effects.

心脏的压力负荷长期增加会导致心脏肥大，最终导致收缩功能障碍和心力衰竭。这种过渡的基本机制仍然是一个有争议的问题。基于电子传递链（ETC）缺陷的线粒体功能障碍已被提出作为一个关键机制。我们和其他人证明了受损的呼吸能力，特别是与复杂的I，收缩功能障碍的发病前。因此，呼吸链复合物是一个有吸引力的治疗靶点。在早期的研究中，我们已经证明，在Gracile综合征小鼠中，通过替代氧化酶（AOX）绕过有缺陷的呼吸复合物III可以预防致命性心肌病的发展。我们在这里建议使用Ndi1，一个单一的亚基NADH脱氢酶的酿酒酵母，绕过复合物I在大鼠模型的肥大和心脏衰竭引起的横向主动脉缩窄（TAC）。我们产生了专门为此目的组成型表达Ndi 1的大鼠。值得注意的是，Ndi 1以非质子动力学方式将电子直接从NADH转移到泛醌，从而降低ETC效率。然而，如果氧和还原当量丰富，则络合物III和IV可以补偿络合物I活性的损失。使用Ndi 1，我们因此期望防止由TAC引起的压力负荷后收缩功能障碍的发作。因此，拟议的研究有三个目的。(1)我们将测试一个激烈争论的压力引起的心力衰竭的原因（即，复合物I中的可能缺陷）。(2)我们可以为新的治疗概念奠定基础，即，通过替代酶如Ndi 1绕过受损的呼吸复合物。(3)我们解决了一个古老的，但从未被证明的范例，其中“临界心脏质量”被认为是由于增加氧扩散距离在肥大的发展过程中造成局部缺氧。由于Ndi 1的活性需要充足的氧气，我们可能会发现区域缺氧是否参与心力衰竭的发展过程，因为缺氧不会让Ndi 1引起减轻疾病的作用。