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MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents.

ABSTRACT: An innovative approach for cardiac regeneration following injury is to induce endogenous cardiomyocyte (CM) cell cycle re-entry. In the present study, CMs from adult rat hearts were isolated and transfected with cel-miR-67 (control) and rno-miR-210. A significant increase in CM proliferation and mono-nucleation were observed in miR-210 group, in addition to a reduction in CM size, multi-nucleation, and cell death. When compared to control, ?-catenin and Bcl-2 were upregulated while APC (adenomatous polyposis coli), p16, and caspase-3 were downregulated in miR-210 group. In silico analysis predicted cell cycle inhibitor, APC, as a direct target of miR-210 in rodents. Moreover, compared to control, a significant increase in CM survival and proliferation were observed with siRNA-mediated inhibition of APC. Furthermore, miR-210 overexpressing C57BL/6 mice (210-TG) were used for short-term ischemia/reperfusion study, revealing smaller cell size, increased mono-nucleation, decreased multi-nucleation, and increased CM proliferation in 210-TG hearts in contrast to wild-type (NTG). Likewise, myocardial infarction (MI) was created in adult mice, echocardiography was performed, and the hearts were harvested for immunohistochemistry and molecular studies. Compared to NTG, 210-TG hearts showed a significant increase in CM proliferation, reduced apoptosis, upregulated angiogenesis, reduced infarct size, and overall improvement in cardiac function following MI. ?-catenin, Bcl-2, and VEGF (vascular endothelial growth factor) were upregulated while APC, p16, and caspase-3 were downregulated in 210-TG hearts. Overall, constitutive overexpression of miR-210 rescues heart function following cardiac injury in adult mice via promoting CM proliferation, cell survival, and angiogenesis. KEY MESSAGES:MiRNA-210 transfected adult rat CMs show proliferation and reduced cell death in vitro. Cell cycle inhibitor APC is a target of miR-210. MiR-210 overexpressing (210-TG) mouse hearts show CMs cell cycle re-entry and survival post myocardial injury. 210-TG mice show significant neovascularization and angiogenic potential post myocardial infarction. 210-TG hearts show reduced infarct size following ischemic injury.

SUBMITTER: Arif M

PROVIDER: S-EPMC5941944 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents.

Arif Mohammed M Pandey Raghav R Alam Perwez P Jiang Shujia S Sadayappan Sakthivel S Paul Arghya A Ahmed Rafeeq P H RPH

Journal of molecular medicine (Berlin, Germany) 20170925 12

An innovative approach for cardiac regeneration following injury is to induce endogenous cardiomyocyte (CM) cell cycle re-entry. In the present study, CMs from adult rat hearts were isolated and transfected with cel-miR-67 (control) and rno-miR-210. A significant increase in CM proliferation and mono-nucleation were observed in miR-210 group, in addition to a reduction in CM size, multi-nucleation, and cell death. When compared to control, β-catenin and Bcl-2 were upregulated while APC (adenomat ...[more]

PMID: 28948298

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Project description:BackgroundIschemic 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.MethodsMyocardial 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.ResultsMicroRNA-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.ConclusionsMicroRNA-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.

Project description:Objective: This investigation examined the effect of velvet antler (VA) on endothelial progenitor cells (EPCs) and the associated effects to promote angiogenesis and repair vascular endothelial injury in rats with myocardial infarction (MI). Methods: VA was analyzed by liquid chromatography-mass spectrometry. Male Sprague Dawley rats were randomly divided into four groups: sham, MI, VA, and VA + DAPT (gamma-secretase inhibitor IX, a specific blocker of the Notch signaling pathway) group. The rats underwent ligation of the left anterior descending coronary artery for the establishment of MI. Sham-operated rats were used as controls. Blood was taken from the orbital plexus on the first and third days after the operation, and all rats were euthanized on the 7th day after surgery. The blood samples were used to detect the contents of circulating endothelial progenitor cells (CEPCs) and vascular endothelial growth factor (VEGF). Echocardiography was used to test the cardiac function. Cardiac tissue was used for immunohistochemistry and electron microscope, and the marginal zone of the MI tissue was used for western blot and reverse transcription-quantitative polymerase chain reaction. Results: The number of basically qualitative metabolites is 445. Among them, there are 74 substances with relative content greater than 0.05%. VA increased the concentration of CEPCs and VEGF in serum, CD133 content and microvessel density (MVD), and protected the morphology of microvascular endothelial cells in the marginal area of MI at 7 days post-MI surgery. CEPCs and MVD in the VA +DAPT group were lower than those of VA group. VA increased the protein expressions of Jagged-1, Notch1, NICD and HES1, and the mRNA expressions of Hes1 and Hey2, while some of the effects could be suppressed by DAPT. Conclusion: These results suggest that VA promotes the mobilization of EPCs to promote angiogenesis and repair vascular endothelial cell damage in post-MI rats, and these effects may be due to activation of the Notch signal pathway.

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MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents.

Publications

MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents.

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