期刊
CARDIOVASCULAR RESEARCH
卷 84, 期 3, 页码 396-406出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvp251
关键词
Arrhythmia; L-type calcium channel; Cardiac fibrosis; Hypertrophy; Heart failure; Transgenic mice
资金
- Deutsche Forschungsgemeinschaft [EXC294]
- Center of Molecular Medicine
- NIH [R01 HL 079599]
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 beta(2)-subunits is enhanced in human failing hearts. In order to determine whether prolonged alteration of Ca2+-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. 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 Ca2+-current density at more negative test potentials. Activity of single Ca2+-channels was increased in myocytes isolated from beta(2a)-transgenic mice. Ca2+-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. Cardiac overexpression of a Ca2+-channel beta(2a)-subunit alone is sufficient to induce Ca2+-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.
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