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.
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This work was supported by the National Natural Science Foundation of China (30730045, 31010103911) and the National Basic Research Program of China (973 Program, 2007CB512000, 2011CB965300). pαMHC-clone26 was kindly provided by Z. Yang (Nanjing University). CnAα and CnAβ cDNAs were kindly provided by T. Kuno (Kobe University). The antibody to phospho-Drp1 (Ser656) was kindly provided by S. Strack (University of Iowa).
The authors declare no competing financial interests.
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Wang, JX., Jiao, JQ., Li, Q. et al. miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nat Med 17, 71–78 (2011). https://doi.org/10.1038/nm.2282
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