Abstract
Background miR-205 is important for oxidative stress, mitochondrial dysfunction, and apoptosis. The roles of miR-205 in cardiac ischemia/reperfusion (I/R) injury remain unknown. The aim of this research is to reveal whether miR-205 could regulate cardiac I/R injury by focusing upon the oxidative stress, mitochondrial function, and apoptosis. Methods Levels of miR-205 and Rnd3 were examined in the hearts with I/R injury. Myocardial infarct size, cardiac function, oxidative stress, mitochondria function, and cardiomyocyte apoptosis were detected in mice with myocardial ischemia/reperfusion (MI/R) injury. The primary neonatal cardiomyocytes underwent hypoxia/reoxygenation (H/R) to simulate MI/R injury. Results miR-205 levels were significantly elevated in cardiac tissues from I/R in comparison with those from Sham. In comparison with controls, levels of Rnd3 were significantly decreased in the hearts from mice with MI/R injury. Furthermore, inhibiting miR-205 alleviated MI/R-induced apoptosis, reduced infarct size, prevented oxidative stress increase and mitochondrial fragmentation, and improved mitochondrial functional capacity and cardiac function. Consistently, overexpression of miR-205 increased infarct size and promoted apoptosis, oxidative stress, and mitochondrial dysfunction in mice with MI/R injury. In cultured mouse neonatal cardiomyocytes, downregulation of miR-205 reduced oxidative stress in H/R-treated cardiomyocytes. Finally, inhibiting Rnd3 ablated the cardioprotective effects of miR-205 inhibitor in MI/R injury. Conclusions We conclude that inhibiting miR-205 reduces infarct size, improves cardiac function, and suppresses oxidative stress, mitochondrial dysfunction, and apoptosis by promoting Rnd3 in MI/R injury. miR-205 inhibitor-induced Rnd3 activation is a valid target to treat MI/R injury.
Highlights
Despite remarkable progress in disease prevention, diagnosis, and better control of risk factors, heart disease remains the most major contributor to mortality and morbidity worldwide [1, 2]
We found that inhibiting miR-205 improved cardiac dysfunction and mitochondrial dysfunction and reduced infarct size, oxidative stress, and apoptosis by promoting Rnd3 in myocardial ischemia/reperfusion (MI/R) injury
We found that miR-205 inhibitor improved mitochondrial dysfunction, which was associated with impaired cardiac function
Summary
Despite remarkable progress in disease prevention, diagnosis, and better control of risk factors, heart disease remains the most major contributor to mortality and morbidity worldwide [1, 2]. Though coronary heart disease (CHD) mortality declined about 1%-1.8% annually in the past 20 years, thanks to percutaneous coronary intervention, estimated years of life lost because of MI are still very high [5] Such circumstance indicates that great effort is still needed in research into alleviating cardiac I/R injury. Mitochondrial quality surveillance may be a therapeutic target in myocardial infraction [20] Taken together, this evidence demonstrate that cardiac restoration post injury is greatly related to mitochondrial function. Under stress, RND3 could stabilize HIF1α and promote VEGF expression [31] This cardioprotective effect of RND3 is evidenced by reserved cardiac function of Rnd transgenic mice exposed to pressure overload. No efforts have been made to explore the effects of miR205/Rnd in MI/R injury
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