Genetic reduction of L-type Ca2+ channel activity in mice unexpectedly exacerbated cardiac hypertrophy, ventricular dilation, and heart failure in response to stress stimuli.
Does decreased cardiac L-type Ca2+ channel activity protect against or induce hypertrophy and heart failure in mice?
Decreased cardiac L-type Ca2+ channel activity induces compensatory neuroendocrine stress and leaky sarcoplasmic reticulum Ca2+ release, leading to hypertrophy and heart failure, which provides a mechanistic explanation for the detrimental effects of LTCC blockers in heart failure patients.
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, α1C subunit Cacna1c mice; referred to herein as α1C⁻/⁺ mice) and mice in which this gene was loxP targeted to achieve graded heart-specific gene deletion (termed herein α1C-loxP mice). Adult cardiomyocytes from the hearts of α1C⁻/⁺ 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, α1C⁻/⁺ mice subjected to pressure overload stimulation, isoproterenol infusion, and swimming showed greater cardiac hypertrophy, greater reductions in ventricular performance, and greater ventricular dilation than α1C⁺/⁺ controls. The same detrimental effects were observed in α1C-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 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.
Goonasekera et al. (Fri,) conducted a other in Cardiac hypertrophy and heart failure. Genetic reduction of L-type Ca2+ channel activity (Cacna1c deletion) vs. Wild-type or control mice was evaluated on Cardiac hypertrophy and ventricular performance. Genetic reduction of L-type Ca2+ channel activity in mice unexpectedly exacerbated cardiac hypertrophy, ventricular dilation, and heart failure in response to stress stimuli.