Transient receptor potential channels contribute to pathological structural and functional remodeling after myocardial infarction

Catherine A. Makarewich, Hongyu Zhang, Jennifer Davis, Robert N. Correll, Danielle M. Trappanese, Nicholas E. Hoffman, Constantine D. Troupes, Remus M. Berretta, Hajime Kubo, Muniswamy Madesh, Xiongwen Chen, Erhe Gao, Jeffery D. Molkentin, Steven R. Houser

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

RATIONALE:: The cellular and molecular basis for post-myocardial infarction (MI) structural and functional remodeling is not well understood. OBJECTIVE:: Our aim was to determine if Ca influx through transient receptor potential canonical (TRPC) channels contributes to post-MI structural and functional remodeling. METHODS AND RESULTS:: TRPC1/3/4/6 channel mRNA increased after MI in mice and was associated with TRPC-mediated Ca entry. Cardiac myocyte-specific expression of a dominant-negative (loss-of-function) TRPC4 channel increased basal myocyte contractility and reduced hypertrophy and cardiac structural and functional remodeling after MI while increasing survival in mice. We used adenovirus-mediated expression of TRPC3/4/6 channels in cultured adult feline myocytes to define mechanistic aspects of these TRPC-related effects. TRPC3/4/6 overexpression in adult feline myocytes induced calcineurin (Cn)-nuclear factor of activated T-cells (NFAT)-mediated hypertrophic signaling, which was reliant on caveolae targeting of TRPCs. TRPC3/4/6 expression in adult feline myocytes increased rested state contractions and increased spontaneous sarcoplasmic reticulum Ca sparks mediated by enhanced phosphorylation of the ryanodine receptor. TRPC3/4/6 expression was associated with reduced contractility and response to catecholamines during steady-state pacing, likely because of enhanced sarcoplasmic reticulum Ca leak. CONCLUSIONS:: Ca influx through TRPC channels expressed after MI activates pathological cardiac hypertrophy and reduces contractility reserve. Blocking post-MI TRPC activity improved post-MI cardiac structure and function.

Original languageEnglish (US)
Pages (from-to)567-580
Number of pages14
JournalCirculation research
Volume115
Issue number6
DOIs
StatePublished - Aug 29 2014

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Keywords

  • calcium
  • calcium channels
  • cardiomegaly
  • myocardial infarction
  • transient receptor potential channels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Makarewich, C. A., Zhang, H., Davis, J., Correll, R. N., Trappanese, D. M., Hoffman, N. E., Troupes, C. D., Berretta, R. M., Kubo, H., Madesh, M., Chen, X., Gao, E., Molkentin, J. D., & Houser, S. R. (2014). Transient receptor potential channels contribute to pathological structural and functional remodeling after myocardial infarction. Circulation research, 115(6), 567-580. https://doi.org/10.1161/CIRCRESAHA.115.303831