Role of mitochondria in cardiac ischemia

线粒体在心肌缺血中的作用

• 批准号: 8723873
• 负责人: Peifeng Li
• 金额: $ 38.1万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723873
• 关键词: Animal Model; Apoptosis; Apoptotic; Cardiac; Cardiac Myocytes; Cell Proliferation; Cells; Cessation of life; Crista ampullaris; Cytochromes; Cytosol; Dominant-Negative Mutation; Dynamin; Energy Supply; Functional disorder; Genes; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Ischemia; Kidney; Lead; Maintenance; Mammalian Cell; Mediating; MicroRNAs; Mitochondria; Molecular; Morphogenesis; Myocardial Infarction; Myocardial Ischemia; Organelles; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Physiology; Play; Prevention; Process; Proteins; Publications; RNA Interference; Regulation; Reperfusion Therapy; Reporting; Role; Serum; Skeletal Muscle; Structure; Testing; Therapeutic; Untranslated RNA; Work; base; heart function; innovation; mortality; neoplastic cell; novel; overexpression; prevent; prohibitin; response

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.

概括 心力衰竭是全世界死亡的主要原因。心肌梗塞有 已被证明是心力衰竭的最常见原因。有效的治疗方法 需要制定预防和治疗心肌梗塞的策略。 细胞凋亡是心肌梗死的一种死亡形式。为了保持心脏 结构和功能均完好，必须防止细胞凋亡，使心脏 不丢失心肌细胞。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 另一方面参与细胞凋亡的启动。最近的研究有 揭示线粒体异常分裂在调节中起着关键作用 细胞凋亡。然而，线粒体裂变在心脏病中的作用已被证实。 研究较少。此外，线粒体裂变的分子调控 心肌细胞仍然很大程度上未知。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。抑制素是一种心脏丰富的蛋白质。这 抑制素在心脏中的功能尚未阐明。 miRNA 参与 心脏生理和病理的调节，但尚不清楚 miRNA 是否 能够调节线粒体裂变机制。我们已经清楚地观察到 表明抑制素和 miRNA 水平会因氧化应激而改变 心脏缺血。此外，抑制素可以阻止线粒体裂变 心肌细胞凋亡。我们假设 miRNA 和抑制素构成 轴在心脏线粒体裂变和细胞凋亡的调节中。研究下 aim-1 和 aim-2 将表征抑制素是否可以被 miRNA 靶向，并且 它们在线粒体裂变和细胞凋亡中的作用。目标 3 下的研究将探索 抑制素调节线粒体裂变和凋亡的分子机制。 目标 4 下的研究将测试抑制素是否会影响心肌梗塞 由缺血/再灌注引起。这个拟议的项目不仅有助于了解 线粒体裂变及其在心脏中的分子调控，还可以导致进一步 研究开发介入治疗的创新方法 与细胞凋亡相关的心脏病，例如心肌梗塞。

项目成果

MicroRNA-532-3p regulates mitochondrial fission through targeting apoptosis repressor with caspase recruitment domain in doxorubicin cardiotoxicity.

在阿霉素心脏毒性中，MicroRNA-532-3p 通过靶向具有 caspase 募集结构域的凋亡阻遏蛋白来调节线粒体裂变

• DOI: 10.1038/cddis.2015.41
• 发表时间: 2015-03-12
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Wang JX;Zhang XJ;Feng C;Sun T;Wang K;Wang Y;Zhou LY;Li PF
• 通讯作者: Li PF

Knockdown of Mtfp1 can minimize doxorubicin cardiotoxicity by inhibiting Dnm1l-mediated mitochondrial fission.

• DOI: 10.1111/jcmm.13250
• 发表时间: 2017-12
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Aung LHH;Li R;Prabhakar BS;Li P
• 通讯作者: Li P

miR-761 regulates the mitochondrial network by targeting mitochondrial fission factor.

• DOI: 10.1016/j.freeradbiomed.2013.07.009
• 发表时间: 2013-12
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Long, Bo;Wang, Kun;Li, Na;Murtaza, Iram;Xiao, Jing-Ying;Fan, Yuan-Yuan;Liu, Cui-Yun;Li, Wen-Hui;Cheng, Zheng;Li, PeiFeng
• 通讯作者: Li, PeiFeng

The mitochondrial ubiquitin ligase plays an anti-apoptotic role in cardiomyocytes by regulating mitochondrial fission.

• DOI: 10.1111/jcmm.12914
• 发表时间: 2016-12
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Wang J;Aung LH;Prabhakar BS;Li P
• 通讯作者: Li P

miR-23a binds to p53 and enhances its association with miR-128 promoter.

• DOI: 10.1038/srep16422
• 发表时间: 2015-11-10
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Li J;Aung LH;Long B;Qin D;An S;Li P
• 通讯作者: Li P