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

摘要

Antagonists of L-type Ca~(2+) 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, α1C subunit [ Cacna1c mice; referred to herein as α 1C~(–/+) mice]) and mice in which this gene was loxP targeted to achieve graded heart-specific gene deletion (termed herein α 1C-loxP mice). Adult cardiomyocytes from the hearts of α 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, α 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 α 1C~(+/+) controls. The same detrimental effects were observed in α 1C-loxP animals with a cardiomyocyte-specific deletion of one allele. More severe reductions in α1C 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 Ca~(2+) release as a compensatory mechanism to preserve contractility. This state results in calcineurinuclear factor of activated T cells signaling that promotes hypertrophy and disease.