TY - JOUR
T1 - Transient receptor potential channels contribute to pathological structural and functional remodeling after myocardial infarction
AU - Makarewich, Catherine A.
AU - Zhang, Hongyu
AU - Davis, Jennifer
AU - Correll, Robert N.
AU - Trappanese, Danielle M.
AU - Hoffman, Nicholas E.
AU - Troupes, Constantine D.
AU - Berretta, Remus M.
AU - Kubo, Hajime
AU - Madesh, Muniswamy
AU - Chen, Xiongwen
AU - Gao, Erhe
AU - Molkentin, Jeffery D.
AU - Houser, Steven R.
PY - 2014/8/29
Y1 - 2014/8/29
N2 - 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.
AB - 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.
KW - calcium
KW - calcium channels
KW - cardiomegaly
KW - myocardial infarction
KW - transient receptor potential channels
UR - http://www.scopus.com/inward/record.url?scp=84907140944&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907140944&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.115.303831
DO - 10.1161/CIRCRESAHA.115.303831
M3 - Article
C2 - 25047165
AN - SCOPUS:84907140944
SN - 0009-7330
VL - 115
SP - 567
EP - 580
JO - Circulation research
JF - Circulation research
IS - 6
ER -