title: Inhibition of calcineurin and sarcolemmal Ca2+ influx protects cardiac morphology and ventricular function in K(v)4.2N transgenic mice.
abstract: BACKGROUND
  Cardiac-targeted expression of truncated K(v)4.2 subunit (K(v)4.2N) reduces transient outward current (I(to)) density, prolongs action potentials (APs), and enhances contractility in 3- to 4-week-old transgenic mice. By 13 to 15 weeks of age, these mice develop severely impaired cardiac function and signs of heart failure. In this study, we examined whether augmented contractility in K(v)4.2N mice results from elevations in intracellular calcium ([Ca2+]i) secondary to AP prolongation and investigated the putative roles of calcineurin activation in heart disease development of K(v)4.2N mice.
  
  
  RESULTS
  At 3 to 4 weeks of age, L-type Ca2+ influx and peak [Ca2+]i were significantly elevated in K(v)4.2N myocytes compared with control because of AP prolongation. Cardiac calcineurin activity was also significantly elevated in K(v)4.2N mice by 5 weeks of age relative to controls and increased progressively as heart disease developed. This was associated with activation of protein kinase C (PKC)-alpha and PKC-theta but not PKC-epsilon, as well as increases in beta-myosin heavy chain (beta-MHC) and reductions in sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA)-2a expression. Treatment with either cyclosporin A or verapamil prevented increases in heart weight to body weight ratios, interstitial fibrosis, impaired contractility, PKC activation, and changes in the expression patterns of beta-MHC and SERCA2a.
  
  
  CONCLUSIONS
  Our results demonstrate that AP prolongation caused by I(to) reduction results in enhanced Ca2+ cycling and hypercontractility in mice and suggests that elevations in [Ca2+]i via I(Ca,L) and activation of calcineurin play a central role in disease development after I(to) reduction using the K(v)4.2N construct.
authors.affiliation: Department of Physiology and the Division of Cardiology, University Health Network, University of Toronto, Toronto, Canada.
authors.forename: Rajan
authors.initials: R
authors.lastname: Sah
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.forename: The-Tin T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Hae W
authors.initials: HW
authors.lastname: Lim
authors.forename: Alan D
authors.initials: AD
authors.lastname: Wickenden
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Wilson
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
mesh_terms: D000200:Action Potentials; D000818:Animals; D001692:Biological Transport; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D024722:Cardiac Myosins / Q000378:metabolism; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006331:Heart Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011493:Protein Kinase C / Q000378:metabolism; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D051672:Shal Potassium Channels; D016276:Ventricular Function; D014700:Verapamil / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D002121:Calcium Channel Blockers; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels; D014700:Verapamil; D011493:Protein Kinase C; D024722:Cardiac Myosins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium