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

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

研究成果: Article査読

99 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1344-1353
ページ数10
ジャーナルJournal of Clinical Investigation
117
5
DOI
出版ステータスPublished - 2007 5月 1
外部発表はい

ASJC Scopus subject areas

  • 医学(全般)

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