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.
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.
Authors: Hongyu Zhang; Catherine A Makarewich; Hajime Kubo; Wei Wang; Jason M Duran; Ying Li; Remus M Berretta; Walter J Koch; Xiongwen Chen; Erhe Gao; Héctor H Valdivia; Steven R Houser Journal: Circ Res Date: 2012-02-02 Impact factor: 17.367
Authors: H Schleifer; B Doleschal; M Lichtenegger; R Oppenrieder; I Derler; I Frischauf; T N Glasnov; C O Kappe; C Romanin; K Groschner Journal: Br J Pharmacol Date: 2012-12 Impact factor: 9.473
Authors: George Dalton; Sung-Wan An; Saif I Al-Juboori; Nicole Nischan; Joonho Yoon; Evgenia Dobrinskikh; Donald W Hilgemann; Jian Xie; Kate Luby-Phelps; Jennifer J Kohler; Lutz Birnbaumer; Chou-Long Huang Journal: Proc Natl Acad Sci U S A Date: 2017-01-09 Impact factor: 11.205
Authors: Brian Leei Lin; Damian Matera; Julia F Doerner; Nan Zheng; Donato Del Camino; Sumita Mishra; Hong Bian; Svetlana Zeveleva; Xiaoguang Zhen; Nathaniel T Blair; Jayhong A Chong; David P Hessler; Djahida Bedja; Guangshuo Zhu; Grace K Muller; Mark J Ranek; Lynn Pantages; Mary McFarland; Matthew R Netherton; Angela Berry; Diane Wong; Georg Rast; Hu Sheng Qian; Steven M Weldon; Jay J Kuo; Achim Sauer; Chris Sarko; Magdalene M Moran; David A Kass; Steven S Pullen Journal: Proc Natl Acad Sci U S A Date: 2019-04-26 Impact factor: 11.205