Blocking post-MI TRPC activity via a dominant-negative TRPC4 channel reduced hypertrophy and cardiac structural and functional remodeling while increasing survival in mice.
Does blocking TRPC channel activity improve cardiac structural and functional remodeling after myocardial infarction in animal models?
Blocking post-MI TRPC activity improves cardiac structure and function, suggesting TRPC channels as a potential therapeutic target for post-MI remodeling.
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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ leak. CONCLUSIONS: Ca2+ 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.
Makarewich et al. (Mon,) conducted a other in Myocardial Infarction. Dominant-negative TRPC4 channel expression was evaluated on Cardiac structural and functional remodeling and survival. Blocking post-MI TRPC activity via a dominant-negative TRPC4 channel reduced hypertrophy and cardiac structural and functional remodeling while increasing survival in mice.
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