Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle Ca2+ release channel
Naohiro Yamaguchi, … , Oliver Smithies, Gerhard Meissner
Naohiro Yamaguchi, … , Oliver Smithies, Gerhard Meissner
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1344-1353. https://doi.org/10.1172/JCI29515.
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Research Article Cardiology

Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle Ca2+ release channel

Abstract

Studies with isolated membrane fractions have shown that calmodulin (CaM) inhibits the activity of cardiac muscle cell Ca2+ release channel ryanodine receptor 2 (RyR2). To determine the physiological importance of CaM regulation of RyR2, we generated a mouse with 3 amino acid substitutions (RyR2-W3587A/L3591D/F3603A) in exon 75 of the Ryr2 gene, which encodes the CaM-binding site of RyR2. Homozygous mutant mice showed an increased ratio of heart weight to body weight, greatly reduced fractional shortening of the left ventricle, and lethality at 9–16 days of age. Biochemical analysis of hearts of 7- and 10-day-old homozygous mutant mice indicated an impaired CaM inhibition of RyR2 at micromolar Ca2+ concentrations, reduction in RyR2 protein levels and sarcoplasmic reticulum Ca2+ sequestration, and upregulation of genes and/or proteins associated with class II histone deacetylase/myocyte enhancer factor-2 and calcineurin signaling pathways. Sustained Ca2+ transients, often displaying repeated periods of incomplete Ca2+ removal, were observed in homozygous cardiomyocytes. Taken together, the data indicate that impaired CaM inhibition of RyR2, associated with defective sarcoplasmic reticulum Ca2+ release and altered gene expression, leads to cardiac hypertrophy and early death.

Authors

Naohiro Yamaguchi, Nobuyuki Takahashi, Le Xu, Oliver Smithies, Gerhard Meissner

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Figure 1

Body weights, heart weight to body weight ratios, and survival of WT and mutant mice.

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Body weights, heart weight to body weight ratios, and survival of WT and...
(A) H&E-stained heart sections of 10-day-old WT and mutant mice. Scale bar: 1 mm. (B) Body weights and (C) heart weight to body weight ratios of WT and mutant mice. Data are mean ± SEM of 25–150 (1- to 10-day-old) or 11–14 (13-week-old) mice. *P < 0.05, #P < 0.0001 compared with WT. (D) Survival of WT and mutant mice after 10 days. Data for 10 WT, 15 heterozygous (HET), and 14 homozygous (HOM) mice are shown. The mean survival of homozygous mice was 13.6 ± 0.4 days.