miR-499 protects cardiomyocytes from H 2O 2-induced apoptosis via its effects on Pdcd4 and Pacs2

RNA Biol. 2014;11(4):339-50. doi: 10.4161/rna.28300. Epub 2014 Feb 27.

Abstract

Background microRNAs (miRNAs) are a class of small, non-coding endogenous RNAs that post-transcriptionally regulate some protein-coding genes. miRNAs play an important role in many cardiac pathophysiological processes, including myocardial infarction, cardiac hypertrophy, and heart failure. miR-499, specifically expressed in skeletal muscle and cardiac cells, is differentially regulated and functions in heart development. However, the function of miR-499 in mature heart is poorly understood. Results We report that cardiac-abundant miR-499 could protect neonatal rat cardiomyocytes against H 2O 2-induced apoptosis. Increased miR-499 level favored survival, while decreased miR-499 level favored apoptosis. We identified three proapoptotic protein-coding genes-Pdcd4, Pacs2, and Dyrk2-as targets of miR-499. miR-499 inhibited cardiomyocyte apoptosis through its suppressive effect on Pdcd4 and Pacs2 expression, thereby blocking Bid expression and BID mitochondrial translocation. We also found that H 2O 2-induced phosphorylation of c-Jun transcriptionally upregulated miR-499 expression via binding of phosphorylated c-Jun to the Myh7b promoter. Conclusions Our results revealed that miR-499 played an inhibiting role in the mitochondrial apoptosis pathway, and had protective effects against H 2O 2-induced injury in cardiomyocytes.

Keywords: BID; PACS2; PDCD4; c-Jun; miR-499; mitochondrial apoptosis pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Apoptosis Regulatory Proteins / genetics*
  • BH3 Interacting Domain Death Agonist Protein / genetics
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Hydrogen Peroxide / pharmacology
  • Male
  • MicroRNAs / genetics*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Tyrosine Kinases / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA Interference
  • RNA, Messenger
  • Rats
  • Reactive Oxygen Species
  • Vesicular Transport Proteins / genetics*

Substances

  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • MIRN499 microRNA, rat
  • MicroRNAs
  • Pacs2 protein, rat
  • Pdcd4 protein, rat
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Reactive Oxygen Species
  • Vesicular Transport Proteins
  • Hydrogen Peroxide
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases