Suppression of Cardiac L-Type Ca Channel Activity Causes Cardiac Hypertrophy

Abstract

Increased L type Ca channel (LTCC) activity was proposed to induce Ca dependent hypertrophy and heart failure by activating CaMK and calcineurin (CaN) signaling. Previous experiments showed that upregulation of LTCC activity induced profound cardiomyopathy. However, the enhanced Ca influx did not activate CaN or hypertrophy; but led to necrotic myocyte death. We hypothesized that reducing LTCC by genetic deletion of 50% of Cav1.2 would be cardioprotective like β-adrenergic receptor or LTCC blockers. Surprisingly, this deletion enhanced disease, CaN activation and hypertrophy. These myocytes with reduced Ca current exhibited significantly increased diastolic Ca. To further address these surprising findings we analyzed the Ca dynamics of mice with a standard null allele crossed with a cardiac specific flox allele (α1cf/-Cre), which led to an even greater deletion of the α1c protein in the heart. Here we measured Ca handling dynamics in α1cf/-Cre mice. Twitch amplitudes were significantly reduced (50%) and relaxation time was prolonged (16%). SR Ca load was reduced significantly (∼25%). These findings may be explained by increased diastolic SR Ca leak that we measured in myocytes from α1cf/-Cre mice. Thus, the deletion of the α1c protein in mouse cardiac myocytes leads to an increased basal [Ca]i by increasing Ca leak from the SR. Interestingly, the CaMKII inhibitor KN93 completely reversed the effects of the reduced LTCC: twitch amplitude and relaxation as well as SR Ca load were rescued. These results suggest that resting [Ca]i and the gain in ECC are increased to maintain contractility. This increase might drive hypertrophy by activating CaN and CaMKII.