Cardiovascular Research Advance Access first published online on July 20, 2009
This version [Corrected Proof] published online on August 27, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp251
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Transgenic simulation of human heart failure-like L-type Ca2+-channels: implications for fibrosis and heart rate in mice
1 Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany
2 Centre for Biological Signaling Studies (bioss), University of Freiburg, Freiburg, Germany
3 Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany
4 Department of Pharmacology and Toxicology, University of Saarland, Medical Campus, Homburg, Germany
5 Department of Internal Medicine III, University of Cologne, Cologne, Germany
6 Center of Molecular Medicine, University of Cologne, Cologne, Germany
7 Institute of Molecular Pharmacology and Biophysics, University of Cincinnati College of Medicine, University of Cincinnati, Cincinnati, OH, USA
* Corresponding author. Tel: +49 761 203 5314 (L.H.)/+49 221 478 6064 (S.H.); fax: +49 761 2035318 (L.H.)/+49 221 478 89049 (S.H.). E-mail address: lutz.hein{at}pharmakol.uni-freiburg.de (L.H.)/stefan.herzig{at}uni-koeln.de (S.H.).
Aims: Cardiac L-type Ca2+-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 Ca2+-channel β2-subunits is enhanced in human failing hearts. In order to determine whether prolonged alteration of Ca2+-channel gating by β2-subunits contributes to heart failure pathogenesis, we generated and characterized transgenic mice with cardiac overexpression of a β2a-subunit or the pore Cav1.2 or both, respectively.
Methods and results: Four weeks induction of cardiac-specific overexpression of rat β2a-subunits shifted steady-state activation and inactivation of whole-cell currents towards more negative potentials, leading to increased Ca2+-current density at more negative test potentials. Activity of single Ca2+-channels was increased in myocytes isolated from β2a-transgenic mice. Ca2+-current stimulation by 8-Br-cAMP and okadaic acid was blunted in β2a-transgenic myocytes. In vivo investigation revealed hypotension and bradycardia upon Cav1.2-transgene expression but not in mice only overexpressing β2a. Double-transgenics showed cardiac arrhythmia. Interstitial fibrosis was aggravated by the β2a-transgene compared with Cav1.2-transgene expression alone. Overt cardiac hypertrophy was not observed in any model.
Conclusion: Cardiac overexpression of a Ca2+-channel β2a-subunit alone is sufficient to induce Ca2+-channel properties characteristic of chronic human heart failure. β2a-overexpression by itself did not induce cardiac hypertrophy or contractile dysfunction, but aggravated the development of arrhythmia and fibrosis in Cav1.2-transgenic mice.
KEYWORDS Arrhythmia; L-type calcium channel; Cardiac fibrosis; Hypertrophy; Heart failure; Transgenic mice
Time for primary review: 24 days