Abstract
Myocardial infarction is a leading cause of mortality worldwide. Here we report that modulation of microRNA-499 (miR-499) levels affects apoptosis and the severity of myocardial infarction and cardiac dysfunction induced by ischemia-reperfusion. We found that both the α- and β-isoforms of the calcineurin catalytic subunit are direct targets of miR-499 and that miR-499 inhibits cardiomyocyte apoptosis through its suppression of calcineurin-mediated dephosphorylation of dynamin-related protein-1 (Drp1), thereby decreasing Drp1 accumulation in mitochondria and Drp1-mediated activation of the mitochondrial fission program. We also found that p53 transcriptionally downregulates miR-499 expression. Our data reveal a role for miR-499 in regulating the mitochondrial fission machinery and we suggest that modulation of miR-499 levels may provide a therapeutic approach for treating myocardial infarction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Calcineurin / physiology*
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Dogs
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Dynamins
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / physiology*
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Homeostasis
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Humans
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Mice
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Mice, Transgenic
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MicroRNAs / physiology*
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MicroRNAs / therapeutic use
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / physiology*
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Mitochondria / physiology*
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Mitochondria, Heart / physiology
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / physiology*
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Myocardial Infarction / drug therapy
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Rats
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Reperfusion Injury / drug therapy
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Sequence Alignment
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Transcription, Genetic
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Tumor Suppressor Protein p53 / physiology*
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Ventricular Remodeling / drug effects
Substances
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MIRN499 microRNA, human
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MicroRNAs
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Microtubule-Associated Proteins
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Mitochondrial Proteins
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Tumor Suppressor Protein p53
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Calcineurin
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GTP Phosphohydrolases
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DNM1L protein, human
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Dynamins