Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle Ca2+ release channel
Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle Ca2+ release channel
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DOI：
10.1172/jci29515
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发表时间：
2007-05-01
影响因子：
15.9
通讯作者：
Meissner, Gerhard
中科院分区：
文献类型：
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作者：
Yamaguchi, Naohiro;Takahashi, Nobuyuki;Meissner, Gerhard
分离膜组分的研究表明，钙调素（CaM）抑制心肌细胞Ca2+释放通道ryanodine receptor 2 （RyR2）的活性。为了确定CaM调控RyR2的生理重要性，我们在RyR2基因的第75外显子（编码RyR2的CaM结合位点）上生成了3个氨基酸替换（RyR2- w3587a /L3591D/F3603A）的小鼠。纯合子突变小鼠在9-16日龄时心脏重量与体重之比增加，左心室缩短率大大降低，死亡率降低。7日龄和10日龄纯合子突变小鼠的心脏生化分析表明，在微摩尔Ca2+浓度下，RyR2的CaM抑制受损，RyR2蛋白水平和肌浆网Ca2+隔离减少，与II类组蛋白去乙酰化酶/心肌细胞增强因子-2和钙调神经磷酸酶信号通路相关的基因和/或蛋白质上调。在纯合子心肌细胞中观察到持续的Ca2+瞬态，经常显示重复的不完全Ca2+去除期。综上所述，这些数据表明，RyR2的CaM抑制受损，与肌浆网Ca2+释放缺陷和基因表达改变相关，导致心脏肥厚和早期死亡。
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.