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

Abstract

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 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 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. 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 calcineurin/nuclear factor of activated T cells signaling that promotes hypertrophy and disease.

Dynamic Alterations in the CaV1.2/CaM/CaMKII Signaling Pathway in the Left Ventricular Myocardium of Ischemic Rat Hearts

“…Consistent with our data, the Ca 2 + channel a1c subunit expression decreased dramatically in the ventricle in ischemic hypertrophic myocardium at 6 weeks after MI (Huang et al, 2008;Goonasekera et al, 2012). In the failing mouse heart, the investigators consistently observed a significant reduction in a1c protein after 8 weeks of pressure overload stimulation (Goonasekera et al, 2012).…”

Loss of β-adrenergic–stimulated phosphorylation of Ca V 1.2 channels on Ser1700 leads to heart failure

“…Moreover, Ca V 1.2 blockers effectively inhibit cardiac remodeling and prevent cardiomyopathy in animal models with pressure overload (41,42). Paradoxically, in light of these experimental results, decreased expression of Ca V 1.2 protein in the heart also leads to heart failure (43). In addition to direct effects on Ca 2+ signaling, changes in Ca V 1.2 protein levels also would alter subcellular dyadic structures in cardiomyocytes that depend on the presence of the Ca V 1.2 protein (44-46) and would modify the level and composition of the supramolecular complex of Ca V 1.2 with other signaling proteins such as the β2-adrenergic receptor, AKAPs, adenylyl cyclases, PKA and other kinases, phosphodiesterases, and phosphoprotein phosphatases, including calcineurin (47)(48)(49).…”

Basal and β-adrenergic regulation of the cardiac calcium channel Ca V 1.2 requires phosphorylation of serine 1700

“…This reduced exercise capacity of SA mice, plus the changes in intracellular Ca 2+ signaling that result from reduced basal and stimulated Ca V 1.2 current, likely trigger cardiac hypertrophy in SA mice. Previous studies have shown that many changes in Ca-dependent signaling pathways can induce hypertrophy in experimental animals, including changes in Ca 2+ /calmodulin-dependent protein kinase II activity, calcineurin, level of expression of Ca V 1.2 channels, and regulation of Ca V 1.2 channels (4,5,37,38). Remarkably, simply deleting the dCT of Ca V 1.2 channels is sufficient to cause prenatal cardiac hypertrophy and heart failure (16,17).…”

“…Remarkably, simply deleting the dCT of Ca V 1.2 channels is sufficient to cause prenatal cardiac hypertrophy and heart failure (16,17). Moreover, both increased and decreased expression of Ca V 1.2 channels can cause hypertrophy and heart failure (37,38), suggesting a precise balance point for healthy cardiac function. Our results reveal that mutation of a single amino acid residue that impairs basal and β-adrenergic regulation of Ca V 1.2 channels is sufficient to induce cardiac hypertrophy.…”