RBFox2-miR-34a-Jph2 axis contributes to cardiac decompensation during heart failure

Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6172-6180. doi: 10.1073/pnas.1822176116. Epub 2019 Mar 13.

Abstract

Heart performance relies on highly coordinated excitation-contraction (EC) coupling, and defects in this critical process may be exacerbated by additional genetic defects and/or environmental insults to cause eventual heart failure. Here we report a regulatory pathway consisting of the RNA binding protein RBFox2, a stress-induced microRNA miR-34a, and the essential EC coupler JPH2. In this pathway, initial cardiac defects diminish RBFox2 expression, which induces transcriptional repression of miR-34a, and elevated miR-34a targets Jph2 to impair EC coupling, which further manifests heart dysfunction, leading to progressive heart failure. The key contribution of miR-34a to this process is further established by administrating its mimic, which is sufficient to induce cardiac defects, and by using its antagomir to alleviate RBFox2 depletion-induced heart dysfunction. These findings elucidate a potential feed-forward mechanism to account for a critical transition to cardiac decompensation and suggest a potential therapeutic avenue against heart failure.

Keywords: EC coupling; Jph2; RBFox2; heart failure; miR-34a.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Down-Regulation
  • Heart / physiopathology*
  • Heart Failure / metabolism*
  • Heart Failure / physiopathology
  • Humans
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • MicroRNAs / metabolism*
  • Muscle Proteins / metabolism*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / physiology
  • RNA Splicing Factors / metabolism*

Substances

  • MIRN34a microRNA, mouse
  • Membrane Proteins
  • MicroRNAs
  • Muscle Proteins
  • RNA Splicing Factors
  • Rbfox2 protein, mouse
  • junctophilin-2 protein, mouse