TRPC channels are necessary mediators of pathologic cardiac hypertrophy

Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):7000-5. doi: 10.1073/pnas.1001825107. Epub 2010 Mar 29.

Abstract

Pathologic hypertrophy of the heart is regulated through membrane-bound receptors and intracellular signaling pathways that function, in part, by altering Ca(2+) handling and Ca(2+)-dependent signaling effectors. Transient receptor potential canonical (TRPC) channels are important mediators of Ca(2+)-dependent signal transduction that can sense stretch or activation of membrane-bound receptors. Here we generated cardiac-specific transgenic mice that express dominant-negative (dn) TRPC3, dnTRPC6, or dnTRPC4 toward blocking the activity of the TRPC3/6/7 or TRPC1/4/5 subfamily of channels in the heart. Remarkably, all three dn transgenic strategies attenuated the cardiac hypertrophic response following either neuroendocrine agonist infusion or pressure-overload stimulation. dnTRPC transgenic mice also were partially protected from loss of cardiac functional performance following long-term pressure-overload stimulation. Importantly, adult myocytes isolated from hypertrophic WT hearts showed a unique Ca(2+) influx activity under store-depleted conditions that was not observed in myocytes from hypertrophied dnTRPC3, dnTRPC6, or dnTRPC4 hearts. Moreover, dnTRPC4 inhibited the activity of the TRPC3/6/7 subfamily in the heart, suggesting that these two subfamilies function in coordinated complexes. Mechanistically, inhibition of TRPC channels in transgenic mice or in cultured neonatal myocytes significantly reduced activity in the calcineurin-nuclear factor of activated T cells (NFAT), a known Ca(2+)-dependent hypertrophy-inducing pathway. Thus, TRPC channels are necessary mediators of pathologic cardiac hypertrophy, in part through a calcineurin-NFAT signaling pathway.

Publication types

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

MeSH terms

  • Animals
  • Calcineurin / metabolism
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology*
  • Echocardiography / methods
  • Genes, Dominant
  • Mice
  • Mice, Transgenic
  • Myocytes, Cardiac / metabolism
  • NFATC Transcription Factors / metabolism
  • Promoter Regions, Genetic
  • Signal Transduction
  • TRPC Cation Channels / metabolism
  • TRPC6 Cation Channel
  • Transient Receptor Potential Channels / metabolism
  • Transient Receptor Potential Channels / physiology*

Substances

  • NFATC Transcription Factors
  • TRPC Cation Channels
  • TRPC3 cation channel
  • TRPC6 Cation Channel
  • Transient Receptor Potential Channels
  • Trpc6 protein, mouse
  • Trpc7 protein, mouse
  • Calcineurin