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In Vivo Nanovector Delivery of a Heart-specific MicroRNA-sponge
Published on: June 15, 2018
MicroRNA-210 Controls Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction
Rui Song1, Chiranjib Dasgupta1, Cassidy Mulder1
1Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, CA.
Background:
Ischemic heart disease remains a leading cause of death worldwide. In this study, we test the hypothesis that microRNA-210 protects the heart from myocardial ischemia-reperfusion (IR) injury by controlling mitochondrial bioenergetics and reactive oxygen species (ROS) flux.
Methods:
Myocardial infarction in an acute setting of IR was examined through comparing loss- versus gain-of-function experiments in microRNA-210-deficient and wild-type mice. Cardiac function was evaluated by echocardiography. Myocardial mitochondria bioenergetics was examined using a Seahorse XF24 Analyzer.
Results:
MicroRNA-210 deficiency significantly exaggerated cardiac dysfunction up to 6 weeks after myocardial IR in male, but not female, mice. Intravenous injection of microRNA-210 mimic blocked the effect and recovered the increased myocardial IR injury and cardiac dysfunction. Analysis of mitochondrial metabolism revealed that microRNA-210 inhibited mitochondrial oxygen consumption, increased glycolytic activity, and reduced mitochondrial ROS flux in the heart during IR injury. Inhibition of mitochondrial ROS with MitoQ consistently reversed the effect of microRNA-210 deficiency. Mechanistically, we showed that mitochondrial glycerol-3-phosphate dehydrogenase is a novel target of microRNA-210 in the heart, and loss-of-function and gain-of-function experiments revealed that glycerol-3-phosphate dehydrogenase played a key role in the microRNA-210-mediated effect on mitochondrial metabolism and ROS flux in the setting of heart IR injury. Knockdown of glycerol-3-phosphate dehydrogenase negated microRNA-210 deficiency-induced increases in mitochondrial ROS production and myocardial infarction and improved left ventricular fractional shortening and ejection fraction after the IR treatment.
Conclusions:
MicroRNA-210 targeting glycerol-3-phosphate dehydrogenase controls mitochondrial bioenergetics and ROS flux and improves cardiac function in a murine model of myocardial infarction in the setting of IR injury. The findings suggest new insights into the mechanisms and therapeutic targets for treatment of ischemic heart disease.
Insights
MicroRNA-210 protects the heart from ischemia-reperfusion injury by regulating mitochondrial function and reducing harmful reactive oxygen species (ROS). This discovery offers new therapeutic targets for ischemic heart disease.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Molecular Cardiology
Background:
- Ischemic heart disease is a major global cause of mortality.
- Myocardial ischemia-reperfusion (IR) injury contributes significantly to heart damage.
- Understanding protective mechanisms against IR injury is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the protective role of microRNA-210 against myocardial IR injury.
- To elucidate the mechanisms by which microRNA-210 influences mitochondrial bioenergetics and reactive oxygen species (ROS) flux.
- To identify novel therapeutic targets for mitigating IR-induced cardiac dysfunction.
Main Methods:
- Utilized a murine model of myocardial IR injury, comparing microRNA-210-deficient and wild-type mice.
- Assessed cardiac function using echocardiography.
- Analyzed mitochondrial bioenergetics and ROS production via Seahorse XF24 Analyzer and other assays.
Main Results:
- MicroRNA-210 deficiency exacerbated cardiac dysfunction and myocardial infarction post-IR, particularly in male mice.
- MicroRNA-210 inhibited mitochondrial oxygen consumption, enhanced glycolysis, and reduced mitochondrial ROS.
- Glycerol-3-phosphate dehydrogenase was identified as a novel cardiac target of microRNA-210, mediating its effects on mitochondrial metabolism and ROS.
Conclusions:
- MicroRNA-210, by targeting glycerol-3-phosphate dehydrogenase, regulates mitochondrial bioenergetics and ROS flux, thereby improving cardiac function in IR injury.
- These findings provide novel insights into the pathogenesis of ischemic heart disease.
- MicroRNA-210 and glycerol-3-phosphate dehydrogenase represent potential therapeutic targets for treating myocardial IR injury.
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