title: Decreased cardiac L-type Ca²⁺ channel activity induces hypertrophy and heart failure in mice.
abstract: 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.
authors: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, Ohio 45229, USA.
authors: Sanjeewa A
authors: SA
authors: Goonasekera
authors: Karin
authors: K
authors: Hammer
authors: Mannix
authors: M
authors: Auger-Messier
authors: Ilona
authors: I
authors: Bodi
authors: Xiongwen
authors: X
authors: Chen
authors: Hongyu
authors: H
authors: Zhang
authors: Steven
authors: S
authors: Reiken
authors: John W
authors: JW
authors: Elrod
authors: Robert N
authors: RN
authors: Correll
authors: Allen J
authors: AJ
authors: York
authors: Michelle A
authors: MA
authors: Sargent
authors: Franz
authors: F
authors: Hofmann
authors: Sven
authors: S
authors: Moosmang
authors: Andrew R
authors: AR
authors: Marks
authors: Steven R
authors: SR
authors: Houser
authors: Donald M
authors: DM
authors: Bers
authors: Jeffery D
authors: JD
authors: Molkentin
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000172:deficiency* / Q000235:genetics; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006333:Heart Failure / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D009490:Neurosecretory Systems / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D019703:Calcineurin