ArticleThe Journal of clinical investigation2012
Decreased cardiac L-type Ca²⁺ channel activity induces hypertrophy and heart failure in mice.
Article in The Journal of clinical investigation, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 103 papers.
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Who cites it
103 citing papers in PubMed, 164 citations in OpenAlex.
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- Phosphoinositide Depletion and Compensatory Phospho-Signaling in Angiotensin II-Induced Heart Disease.Circulation research · 2026Article
- Multiscale stochastic modeling for calcium dynamics in cardiac electrophysiology: assessing whole-cell model reliability under phosphorylation and LCC downregulation.Frontiers in network physiology · 2026Article
- Cardiovascular inhalation for targeted drug delivery in cardiac disease.Heart failure reviews · 2025Review
- Opposite effects of GαNaunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Maintenance and Reversibility of Paroxysmal Atrial Fibrillation in JDP2 Overexpressing Mice.Cells · 2025Article
- Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity.NPJ Regenerative medicine · 2025Article
- Altered Protein Kinase A-Dependent Phosphorylation of Cav1.2 in Left Ventricular Myocardium fromInternational journal of molecular sciences · 2024Article
- Understanding the Role of Galectin-1 in Heart Failure: A Comprehensive Narrative Review.Current cardiology reviews · 2024Review
- Myocardial Calcium Handling in Type 2 Diabetes: A Novel Therapeutic Target.Journal of cardiovascular development and disease · 2023Review
- Mettl13 protects against cardiac contractile dysfunction by negatively regulating C-Cbl-mediated ubiquitination of SERCA2a in ischemic heart failure.Science China. Life sciences · 2023Article
- Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity.Research square · 2023Article
- Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.Biomolecules · 2023Review
- Novel Roles for the Transcriptional Repressor E4BP4 in Both Cardiac Physiology and Pathophysiology.JACC. Basic to translational science · 2023Article
- Calcium Handling Remodeling Underlies Impaired Sympathetic Stress Response in Ventricular Myocardium fromInternational journal of molecular sciences · 2023Article
- Rapid Pacing Decreases L-type CaThe Journal of membrane biology · 2023Article
- Article
- Modulation of CaHandbook of experimental pharmacology · 2023Article
- Models of the cardiac L-type calcium current: A quantitative review.WIREs mechanisms of disease · 2023Review
43 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 5 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.