Role of mitochondria in cardiac ischemia

描述（由申请人提供）： 总结心力衰竭是全球死亡的主要原因。心肌梗死已被证明是心力衰竭的最常见原因。心肌梗死的预防和治疗需要制定有效的治疗策略。细胞凋亡是心肌梗死的一种死亡形式。为了保持心脏在结构和功能上的完整性，有必要防止细胞凋亡，使心脏不失去心肌细胞。众所周知，心肌细胞富含线粒体。线粒体一方面为心脏功能提供能量，另一方面参与细胞凋亡的启动。近年来的研究表明，线粒体异常分裂在细胞凋亡的调控中起着重要的作用。然而，线粒体分裂在心脏疾病中的作用研究较少。此外，心肌细胞中线粒体分裂的分子调控在很大程度上仍然未知。我们的长期目标是研究线粒体在心脏病理生理学中的作用。Prohibitin是一种心脏丰富的蛋白质。抑制素在心脏中的功能尚未阐明。miRNAs参与心脏生理和病理的调节，但miRNAs是否能够调节线粒体分裂机制尚不清楚。我们的观察结果清楚地表明，抑制素和miRNA水平的改变，以响应氧化应激和心肌缺血。此外，抑制素可以防止心肌细胞线粒体分裂和凋亡。我们推测miRNA和抑制素在心脏线粒体分裂和凋亡的调节中构成了一个轴。在aim-1和aim-2下的研究将表征prohibitin是否可以被miRNA靶向，以及它们在线粒体分裂和凋亡中的作用。目标3的研究将探讨抑制素调控线粒体分裂和凋亡的分子机制。目的-4下的研究将测试prohibitin是否可以影响缺血/再灌注引起的心肌梗死。该项目不仅有助于了解心脏线粒体分裂及其分子调控，还可以进一步研究开发心肌梗死等心脏病相关心脏疾病介入治疗的创新方法。 公共卫生相关性： 心力衰竭是世界范围内死亡的主要原因。心肌梗死已被证明是心力衰竭的最常见原因。心肌梗死的预防和治疗需要制定有效的治疗策略。细胞凋亡是心肌梗死后的一种死亡形式，因此有必要预防心肌细胞凋亡。心肌细胞富含线粒体。然而，线粒体一方面为心脏功能提供能量，另一方面参与细胞凋亡的启动。近年来的研究表明，线粒体异常分裂在细胞凋亡的调控中起着重要的作用。我们的项目有望揭示线粒体分裂在心肌细胞凋亡中的作用。所获得的结果可以导致进一步的研究，以开发创新的方法，介入治疗与心脏病相关的心脏疾病，如心肌梗死。

DESCRIPTION (provided by applicant): Summary Heart failure is a leading cause of mortality worldwide. Myocardial infarction has been proved to be the most common cause of heart failure. The effective therapeutic strategies need to be developed for the prevention and treatment of myocardial infarction. Apoptosis is a type of death form in myocardial infarction. In order to maintain the heart intact in both structure and function, it is necessary to prevent apoptosis so that the heart does not lose cardiomyocytes. It is well known that cardiomyocytes are enriched in mitochondria. Mitochondria on one hand supply energy for the heart function, they on the other hand participate in the initiation of apoptosis. The most recent studies have revealed that mitochondrial abnormal fission plays a critical role in the regulation of apoptosis. However, the role of mitochondrial fission in the cardiac diseases has been less studied. Furthermore, the molecular regulation of mitochondrial fission in cardiomyocytes remains largely unknown. Our long term goal is to study the role of mitochondria in cardiac pathophysiology. Prohibitin is a cardiac abundant protein. The function of prohibitin in the heart has not yet been clarified. miRNAs are involved in the regulation of cardiac physiology and pathology, but it is unknown whether miRNAs are able to regulate mitochondrial fission machinery. We have made observations clearly showing that prohibitin and miRNA levels are altered in response to oxidative stress and cardiac ischemia. Furthermore, prohibitin can prevent mitochondrial fission and apoptosis in cardiomyocytes. We hypothesize that miRNA and prohibitin constitute an axis in the regulation of mitochondrial fission and apoptosis in the heart. Studies under aim-1 and aim-2 will characterize whether prohibitin can be targeted by the miRNA, and their roles in mitochondrial fission and apoptosis. Studies under aim-3 will explore the molecular mechanism by which prohibitin regulate mitochondrial fission and apoptosis. Studies under aim-4 will test whether prohibitin can influence myocardial infarction induced by ischemia/reperfusion. This proposed project will not only help understand mitochondrial fission and its molecular regulation in the heart, but also can lead to further studies to develop the innovative approaches for the interventional treatment of apoptosis-related cardiac diseases such as myocardial infarction. PUBLIC HEALTH RELEVANCE: Project Narrative Heart failure is a leading cause of mortality worldwide. Myocardial infarction has been proved to be the most common cause of heart failure. The effective therapeutic strategies need to be developed for the prevention and treatment of myocardial infarction. Apoptosis is a type of death form in myocardial infarction, it is thus necessary to prevent apoptosis in the heart. Cardiomyocytes are enriched in mitochondria. However, mitochondria on one hand supply energy for the heart function, they on the other hand participate in the initiation of apoptosis. The most recent studies have revealed that mitochondrial abnormal fission plays a critical role in the regulation of apoptosis. Our proposed project is expected to reveal the role of mitochondrial fission in the cardiac apoptosis. The obtained results can lead to further studies to develop the innovative approaches for the interventional treatment of apoptosis-related cardiac diseases such as myocardial infarction.