Decreased cardiac L-type [Ca.sup.2+] channel activity induces hypertrophy and heart failure in mice

Antagonists of L-type [Ca.sup.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 α1[C.sup.+/-] 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 α1[C.sup.-/+] 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, α1[C.sup.+/-] mice subjected to pressure overload stimulation, isoproterenol infusion, and swimming showed greater cardiac hypertrophy, greater reductions in ventricular performance, and greater ventricular dilation than α1[C.sup.+/-] controls. The same detrimental effects were observed in α1C-loxP animals with a cardiomyocytespecific 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. Mechanisti-cally, our data suggest that a reduction in LTCC current leads to neuroendocrine stress, with sensitized and leaky sarcoplasmic reticulum [Ca.sup.2+] 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.
Introduction Voltage-gated L-type [Ca.sup.2+] channels (LTCCs) are the primary source of [Ca.sup.2+] influx to initiate cardiac excitation-contraction coupling (ECC) (1, 2). The molecular composition of the LTCC in cardiomyocytes includes [...]