Impaired cardiac hypertrophic response in calcineurin Aβ-deficient mice
Impaired cardiac hypertrophic response in calcineurin Aβ-deficient mice
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DOI：
10.1073/pnas.072647999
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发表时间：
2002-04-02
影响因子：
11.1
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
--
作者：
Bueno, OF;Wilkins, BJ;Molkentin, JD
钙调磷酸酶是钙-钙调蛋白调节的丝氨酸-苏氨酸磷酸酶，其通过直接激活活化T细胞的核因子和肌细胞增强因子2转录因子而在多种细胞类型中充当应激应答基因表达的关键诱导剂。在心肌细胞中，钙调神经磷酸酶信号转导与压力超负荷或神经内分泌刺激引起的肥大反应的调节有关。三个独立的基因编码哺乳动物细胞中钙调磷酸酶的催化亚基，CnA α、CnA β和CnA γ。为了评估钙调神经磷酸酶作为肥大调节因子的必要功能，在小鼠中破坏CnAbeta基因。CnA β缺陷小鼠存活，生育能力强，成年后明显正常，但心脏中钙调神经磷酸酶活性降低80%，与基础心脏大小减少12%相关。CnAbeta缺陷小鼠通过压力超负荷、血管紧张素II输注或异丙肾上腺素输注诱导的产生性肥大反应的能力显着受损。与肥大反应相关的标记基因的分析揭示了肥大的分子程序中的部分缺陷。总的来说，这些数据巩固了钙调神经磷酸酶在体内作为心脏肥大生长反应的中央调节器的假设。
Calcineurin is a calcium- calmodulin-regulated, serine-threonine phosphatase that functions as a key inducer of stress responsive gene expression in multiple cell types through a direct activation of nuclear factor of activated T cells and myocyte enhancer factor 2 transcription factors. In cardiomyocytes, calcineurin signaling has been implicated in the regulation of the hypertrophic response caused by pressure overload or neuroendocrine stimulation. Three separate genes encode the catalytic subunit of calcineurin in mammalian cells, CnAalpha, CnAbeta, and CnAgamma. To evaluate the necessary function of calcineurin as a hypertrophic regulatory factor, the CnAbeta gene was disrupted in the mouse. CnAbeta-deficient mice were viable, fertile, and overtly normal well into adulthood, but displayed a 80% decrease in calcineurin enzymatic activity in the heart that was associated with a 12% reduction in basal heart size. CnAbeta-deficient mice were dramatically impaired in their ability to mount a productive hypertrophic response induced by pressure overload, angiotensin II infusion, or isoproterenol infusion. Analysis of marker genes associated with the hypertrophic response revealed a partial defect in the molecular program of hypertrophy. Collectively, these data solidify the hypothesis that calcineurin functions as a central regulator of the cardiac hypertrophic growth response in vivo.