title: Transgenic simulation of human heart failure-like L-type Ca2+-channels: implications for fibrosis and heart rate in mice.
abstract: OBJECTIVE
  Cardiac L-type Ca(2+)-currents show distinct alterations in chronic heart failure, including increased single-channel activity and blunted adrenergic stimulation, but minor changes of whole-cell currents. Expression of L-type Ca(2+)-channel beta(2)-subunits is enhanced in human failing hearts. In order to determine whether prolonged alteration of Ca(2+)-channel gating by beta(2)-subunits contributes to heart failure pathogenesis, we generated and characterized transgenic mice with cardiac overexpression of a beta(2a)-subunit or the pore Ca(v)1.2 or both, respectively.
  
  
  RESULTS
  Four weeks induction of cardiac-specific overexpression of rat beta(2a)-subunits shifted steady-state activation and inactivation of whole-cell currents towards more negative potentials, leading to increased Ca(2+)-current density at more negative test potentials. Activity of single Ca(2+)-channels was increased in myocytes isolated from beta(2a)-transgenic mice. Ca(2+)-current stimulation by 8-Br-cAMP and okadaic acid was blunted in beta(2a)-transgenic myocytes. In vivo investigation revealed hypotension and bradycardia upon Ca(v)1.2-transgene expression but not in mice only overexpressing beta(2a). Double-transgenics showed cardiac arrhythmia. Interstitial fibrosis was aggravated by the beta(2a)-transgene compared with Ca(v)1.2-transgene expression alone. Overt cardiac hypertrophy was not observed in any model.
  
  
  CONCLUSIONS
  Cardiac overexpression of a Ca(2+)-channel beta(2a)-subunit alone is sufficient to induce Ca(2+)-channel properties characteristic of chronic human heart failure. beta(2a)-overexpression by itself did not induce cardiac hypertrophy or contractile dysfunction, but aggravated the development of arrhythmia and fibrosis in Ca(v)1.2-transgenic mice.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Beetz
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
authors.forename: Janos
authors.initials: J
authors.lastname: Meszaros
authors.forename: Ralf
authors.initials: R
authors.lastname: Gilsbach
authors.forename: Frederico
authors.initials: F
authors.lastname: Barreto
authors.forename: Marcel
authors.initials: M
authors.lastname: Meissner
authors.forename: Uta C
authors.initials: UC
authors.lastname: Hoppe
authors.forename: Arnold
authors.initials: A
authors.lastname: Schwartz
authors.forename: Stefan
authors.initials: S
authors.lastname: Herzig
authors.forename: Jan
authors.initials: J
authors.lastname: Matthes
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D005355:Fibrosis; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D019319:Okadaic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D021122:Protein Subunits; D019319:Okadaic Acid; D015124:8-Bromo Cyclic Adenosine Monophosphate