Decreased cardiac L-type Ca2+ channel activity induces hypertrophy and heart failure in mice

Antagonists of L-type Ca2+ channels (LTCCs) have been used to treat human cardiovascular diseases for decades. However, these inhibitors can have untoward effects in patients with heart failure, and their overall therapeutic profile remains nebulous given differential effects in the vasculature when compared with those in cardiomyocytes. To investigate this issue, we examined mice heterozygous for the gene encoding the pore-forming subunit of LTCC (calcium channel, voltage-dependent, L type, alpha 1C subunit [Cacna1c mice; referred to herein as alpha 1C(-/+) mice]) and mice in which this gene was loxP targeted to achieve graded heart-specific gene deletion (termed herein alpha 1C-loxP mice). Adult cardiomyocytes from the hearts of alpha 1C(-/+) mice at 10 weeks of age showed a decrease in LTCC current and a modest decrease in cardiac function, which we initially hypothesized would be cardioprotective. However, alpha 1C(-/+) mice subjected to pressure overload stimulation, isoproterenol infusion, and swimming showed greater cardiac hypertrophy, greater reductions in ventricular performance, and greater ventricular dilation than alpha 1C(+/+) controls. The same detrimental effects were observed in alpha 1C-loxP animals with a cardiomyocyte-specific deletion of one allele. More severe reductions in alpha 1C protein levels with combinatorial deleted alleles produced spontaneous cardiac hypertrophy before 3 months of age, with early adulthood lethality. Mechanistically, our data suggest that a reduction in LTCC current leads to neuroendocrine stress, with sensitized and leaky sarcoplasmic reticulum Ca2+ release as a compensatory mechanism to preserve contractility. This state results in calcineurin/nuclear factor of activated T cells signaling that promotes hypertrophy and disease.