Transgenic simulation of human heart failure-like L-type Ca 2+-channels: Implications for fibrosis and heart rate in mice

Abstract

AimsCardiac 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 Ca 2+-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 resultsFour 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.ConclusionCardiac 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.