title: Prevention of hypertrophy by overexpression of Kv4.2 in cultured neonatal cardiomyocytes.
abstract: BACKGROUND
  Prolonged action potentials (APs) and decreased transient outward K+ currents (I(to)) are consistent findings in hypertrophic myocardium. However, the connection of these changes with cardiac hypertrophy is unknown. The present study investigated the effects of changes in I(to) and the associated alterations in AP on myocyte hypertrophy induced by phenylephrine.
  
  
  RESULTS
  Chronic incubation of cultured neonatal ventricular rat myocytes (NVRMs) with phenylephrine (PE) reduced I(to) density and prolonged AP duration, leading to a 2-fold increase in the net Ca2+ influx per beat and a 1.4-fold increase in Ca2+-transient amplitude. PE treatment of chronically paced (2-Hz) NVRM also induced increases in cell size, protein/DNA ratio, atrial natriuretic factor mRNA expression, as well as beta/alpha myosin mRNA ratio. These hypertrophic changes were associated with a 2.4-fold increase in activation of nuclear factor of activated T-cells (NFAT), indicating increased activity of the Ca2+-dependent phosphatase calcineurin. Overexpression of Kv4.2 channels using adenovirus prevented the AP duration prolongation as well as the increases in Ca2+ influx and Ca2+-transient amplitude induced by PE. Kv4.2 overexpression also prohibited the PE-induced increases in cell size, protein/DNA ratio, atrial natriuretic factor expression, beta/alpha myosin mRNA ratio, and NFAT activation.
  
  
  CONCLUSIONS
  Our results demonstrate that PE-mediated hypertrophy in NRVMs seems to require I(to) reductions and AP prolongation associated with increased Ca2+ influx and Ca2+ transients as well as calcineurin activation. The clinical implications of these studies and the possible involvement of other signaling pathways are discussed.
authors.affiliation: Department of Physiology, Division of Cardiology University Health Network and Heart & Stroke Richard Lewar Centre, University of Toronto, Ontario, Canada.
authors.forename: Carsten
authors.initials: C
authors.lastname: Zobel
authors.forename: Zameneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: The-Tin T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Yang
authors.initials: Y
authors.lastname: Meng
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000032:analysis; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D024722:Cardiac Myosins / Q000235:genetics / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D017930:Genes, Reporter / Q000502:physiology; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D050778:NFATC Transcription Factors; D010656:Phenylephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D051672:Shal Potassium Channels; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; C497020:Kcnd2 protein, rat; D050778:NFATC Transcription Factors; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D051672:Shal Potassium Channels; D014157:Transcription Factors; D010656:Phenylephrine; D004247:DNA; D019703:Calcineurin; D024722:Cardiac Myosins; D002118:Calcium