Isoproterenol Activates Extracellular Signal–Regulated Protein Kinases in Cardiomyocytes Through Calcineurin
Isoproterenol Activates Extracellular Signal–Regulated Protein Kinases in Cardiomyocytes Through Calcineurin
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DOI：
10.1161/hc2601.090987
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发表时间：
2001-07
期刊：
影响因子：
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通讯作者：
Y. Zou;A. Yao;Weidong Zhu;S. Kudoh;Y. Hiroi;M. Shimoyama;Hiroki Uozumi;O. Kohmoto;Toshiyuki Takahashi
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文献类型：
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作者：
Y. Zou;A. Yao;Weidong Zhu;S. Kudoh;Y. Hiroi;M. Shimoyama;Hiroki Uozumi;O. Kohmoto;Toshiyuki Takahashi
背景-细胞外信号调节激酶（ERK）和钙调神经磷酸酶在心肌肥厚的发生发展中起重要作用。我们在此研究了心肌细胞中钙调神经磷酸酶和ERK之间的关系。方法和结果-异丙肾上腺素激活培养的新生大鼠心肌细胞中的ERK，并且通过EGTA螯合细胞外Ca 2+、硝苯地平阻断L型Ca 2+通道或毒胡萝卜素耗尽细胞内Ca 2+储备来消除激活。在培养的心肌细胞以及小鼠心脏中，异丙肾上腺素诱导的ERK激活也被钙调磷酸酶抑制剂显著抑制。异丙肾上腺素不能激活培养的心肌细胞或过表达钙调神经磷酸酶显性负突变体的小鼠心脏中的ERK。异丙肾上腺素在收缩期和舒张期均升高细胞内Ca 2+水平，并剂量依赖性地激活钙调神经磷酸酶。钙调磷酸酶的抑制也减弱了异丙肾上腺素刺激的Src，Shc和Raf-1激酶的磷酸化。免疫细胞化学显示钙调神经磷酸酶定位于Z带，异丙肾上腺素诱导钙调神经磷酸酶和ERK转位到细胞核。结论钙调神经磷酸酶通过钙释放机制激活细胞内钙，调节异丙肾上腺素诱导的心肌细胞ERK的激活。
Background—Extracellular signal–regulated kinases (ERKs) and calcineurin have been reported to play important roles in the development of cardiac hypertrophy. We examined here the relation between calcineurin and ERKs in cardiomyocytes. Methods and Results—Isoproterenol activated ERKs in cultured cardiomyocytes of neonatal rats, and the activation was abolished by chelation of extracellular Ca2+ with EGTA, blockade of L-type Ca2+ channels with nifedipine, or depletion of intracellular Ca2+ stores with thapsigargin. Isoproterenol-induced activation of ERKs was also significantly suppressed by calcineurin inhibitors in cultured cardiomyocytes as well as in the hearts of mice. Isoproterenol failed to activate ERKs in either the cultured cardiomyocytes or the hearts of mice that overexpress the dominant negative mutant of calcineurin. Isoproterenol elevated intracellular Ca2+ levels at both systolic and diastolic phases and dose-dependently activated calcineurin. Inhibition of calcineurin also attenuated isoproterenol-stimulated phosphorylation of Src, Shc, and Raf-1 kinase. The immunocytochemistry revealed that calcineurin was localized in the Z band, and isoproterenol induced translocation of calcineurin and ERKs into the nucleus. ConclusionsCalcineurin, which is activated by marked elevation of intracellular Ca2+ levels by the Ca2+-induced Ca2+ release mechanism, regulates isoproterenol-induced activation of ERKs in cardiomyocytes.