title: Ca(2+) influx through L-type Ca(2+) channels and transient receptor potential channels activates pathological hypertrophy signaling.
abstract: Common cardiovascular diseases such as hypertension and myocardial infarction require that myocytes develop greater than normal force to maintain cardiac pump function. This requires increases in [Ca(2+)]. These diseases induce cardiac hypertrophy and increases in [Ca(2+)] are known to be an essential proximal signal for activation of hypertrophic genes. However, the source of "hypertrophic" [Ca(2+)] is not known and is the topic of this study. The role of Ca(2+) influx through L-type Ca(2+) channels (LTCC), T-type Ca(2+) channels (TTCC) and transient receptor potential (TRP) channels on the activation of calcineurin (Cn)-nuclear factor of activated T cells (NFAT) signaling and myocyte hypertrophy was studied. Neonatal rat ventricular myocytes (NRVMs) and adult feline ventricular myocytes (AFVMs) were infected with an adenovirus containing NFAT-GFP, to determine factors that could induce NFAT nuclear translocation. Four millimolar Ca(2+) or pacing induced NFAT nuclear translocation. This effect was blocked by Cn inhibitors. In NRVMs Nifedipine (Nif, LTCC antagonist) blocked high Ca(2+)-induced NFAT nuclear translocation while SKF-96365 (TRP channel antagonist) and Nickel (Ni, TTCC antagonist) were less effective. The relative potency of these antagonists against Ca(2+) induced NFAT nuclear translocation (Nif>SKF-96365>Ni) was similar to their effects on Ca(2+) transients and the LTCC current. Infection of NRVM with viruses containing TRP channels also activated NFAT-GFP nuclear translocation and caused myocyte hypertrophy. TRP effects were reduced by SKF-96365, but were more effectively antagonized by Nif. These experiments suggest that Ca(2+) influx through LTCCs is the primary source of Ca(2+) to activate Cn-NFAT signaling in NRVMs and AFVMs. While TRP channels cause hypertrophy, they appear to do so through a mechanism involving Ca(2+) entry via LTCCs.
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Makarewich
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.forename: Remus M
authors.initials: RM
authors.lastname: Berretta
authors.forename: Larry A
authors.initials: LA
authors.lastname: Barr
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism* / Q000502:physiology; D020747:Calcium Channels, T-Type / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D006352:Heart Ventricles / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D050778:NFATC Transcription Factors / Q000378:metabolism; D009532:Nickel / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology; D020257:Ventricular Remodeling
chemical_list: C509958:Cacna1h protein, rat; D065095:Calcineurin Inhibitors; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D007093:Imidazoles; D050778:NFATC Transcription Factors; D050052:TRPC Cation Channels; D009532:Nickel; D019703:Calcineurin; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D009543:Nifedipine; D016559:Tacrolimus