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

Sanjeewa A. Goonasekera, Karin Hammer, Mannix Auger-Messier, Ilona Bodi, Xiongwen Chen, Hongyu Zhang, Steven Reiken, John W. Elrod, Robert N. Correll, Allen J. York, Michelle A. Sargent, Franz Hofmann, Sven Moosmang, Andrew R. Marks, Steven R. Houser, Donald M Bers, Jeffery D. Molkentin

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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.

Original languageEnglish (US)
Pages (from-to)280-290
Number of pages11
JournalJournal of Clinical Investigation
Volume122
Issue number1
DOIs
StatePublished - Jan 3 2012

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Hypertrophy
Heart Failure
Cardiomegaly
Cardiac Myocytes
Alleles
NFATC Transcription Factors
L-Type Calcium Channels
Calcineurin
Gene Deletion
Sarcoplasmic Reticulum
Isoproterenol
Genes
Dilatation
Cardiovascular Diseases
Pressure
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Goonasekera, S. A., Hammer, K., Auger-Messier, M., Bodi, I., Chen, X., Zhang, H., ... Molkentin, J. D. (2012). Decreased cardiac L-type Ca 2+channel activity induces hypertrophy and heart failure in mice. Journal of Clinical Investigation, 122(1), 280-290. https://doi.org/10.1172/JCI58227

Decreased cardiac L-type Ca 2+channel activity induces hypertrophy and heart failure in mice. / Goonasekera, Sanjeewa A.; Hammer, Karin; Auger-Messier, Mannix; Bodi, Ilona; Chen, Xiongwen; Zhang, Hongyu; Reiken, Steven; Elrod, John W.; Correll, Robert N.; York, Allen J.; Sargent, Michelle A.; Hofmann, Franz; Moosmang, Sven; Marks, Andrew R.; Houser, Steven R.; Bers, Donald M; Molkentin, Jeffery D.

In: Journal of Clinical Investigation, Vol. 122, No. 1, 03.01.2012, p. 280-290.

Research output: Contribution to journalArticle

Goonasekera, SA, Hammer, K, Auger-Messier, M, Bodi, I, Chen, X, Zhang, H, Reiken, S, Elrod, JW, Correll, RN, York, AJ, Sargent, MA, Hofmann, F, Moosmang, S, Marks, AR, Houser, SR, Bers, DM & Molkentin, JD 2012, 'Decreased cardiac L-type Ca 2+channel activity induces hypertrophy and heart failure in mice', Journal of Clinical Investigation, vol. 122, no. 1, pp. 280-290. https://doi.org/10.1172/JCI58227
Goonasekera SA, Hammer K, Auger-Messier M, Bodi I, Chen X, Zhang H et al. Decreased cardiac L-type Ca 2+channel activity induces hypertrophy and heart failure in mice. Journal of Clinical Investigation. 2012 Jan 3;122(1):280-290. https://doi.org/10.1172/JCI58227
Goonasekera, Sanjeewa A. ; Hammer, Karin ; Auger-Messier, Mannix ; Bodi, Ilona ; Chen, Xiongwen ; Zhang, Hongyu ; Reiken, Steven ; Elrod, John W. ; Correll, Robert N. ; York, Allen J. ; Sargent, Michelle A. ; Hofmann, Franz ; Moosmang, Sven ; Marks, Andrew R. ; Houser, Steven R. ; Bers, Donald M ; Molkentin, Jeffery D. / Decreased cardiac L-type Ca 2+channel activity induces hypertrophy and heart failure in mice. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 1. pp. 280-290.
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