title: Transient receptor potential channels contribute to pathological structural and functional remodeling after myocardial infarction.
abstract: BACKGROUND
  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.
  
  
  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.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.|Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Makarewich
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.|Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Davis
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Correll
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Trappanese
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.|Biochemistry Department, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Hoffman
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.|Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Constantine D
authors.initials: CD
authors.lastname: Troupes
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Remus M
authors.initials: RM
authors.lastname: Berretta
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.|Biochemistry Department, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.|Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Howard Hughes Medical Institute, Cincinnati, OH 45229, USA.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.|Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology; D002415:Cats; D002478:Cells, Cultured; D004195:Disease Models, Animal; D056966:Excitation Contraction Coupling / Q000502:physiology; D051379:Mice; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology* / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000473:pathology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D050051:Transient Receptor Potential Channels; D002118:Calcium
keywords: calcium; calcium channels; cardiomegaly; myocardial infarction; transient receptor potential channels