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

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102202-03
Application #
8383493
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2010-12-15
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$368,190
Indirect Cost
$130,190
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Wang, K; Liu, F; Zhou, L-Y et al. (2013) miR-874 regulates myocardial necrosis by targeting caspase-8. Cell Death Dis 4:e709
Lu, Daoyuan; Liu, Jinping; Jiao, Jianqin et al. (2013) Transcription factor Foxo3a prevents apoptosis by regulating calcium through the apoptosis repressor with caspase recruitment domain. J Biol Chem 288:8491-504