The calcineurin-myocyte enhancer factor 2c pathway mediates cardiac hypertrophy induced by endoplasmic reticulum stress in neonatal rat cardiomyocytes.
The calcineurin-myocyte enhancer factor 2c pathway mediates cardiac hypertrophy induced by endoplasmic reticulum stress in neonatal rat cardiomyocytes.
复制标题
DOI：
10.1152/ajpheart.00980.2009
复制
发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
Zhen-Ying Zhang;Xiuhua Liu;Weiqing Hu;Fei Rong;Xudong Wu
中科院分区：
文献类型：
--
作者：
Zhen-Ying Zhang;Xiuhua Liu;Weiqing Hu;Fei Rong;Xudong Wu
内质网应激（Endoplasmic reticulum stress，ERS）参与多种心血管疾病的发生。我们前期的研究证实ERS参与了心肌肥厚的发生发展，但其机制尚不清楚。本研究旨在探讨钙调神经磷酸酶（CaN）信号通路在ERS诱导剂毒胡萝卜素（TG）诱导的新生大鼠心肌细胞肥大中的作用。研究ER伴侣蛋白表达，ER染色，钙网蛋白免疫荧光检测ERS反应。采用心钠素和脑钠素mRNA表达、总蛋白合成率和细胞表面积评价TG诱导的心肌肥厚。TG诱导心肌细胞出现明显的ERS反应，沿着肥大，且呈剂量和时间依赖性，这一点通过另一种ERS诱导剂衣霉素的处理得到证实。此外，TG诱导心肌细胞内Ca（2+）水平显著升高，CaN活化，心肌细胞增强因子2c（MEF 2c）表达呈剂量和时间依赖性。CaN抑制剂环孢霉素A可明显抑制MEF 2c核转位，抑制TG诱导的心肌肥大。这些结果表明，ERS诱导心肌肥大，CaN-MEF 2c途径参与ERS诱导的心肌细胞肥大。
Endoplasmic reticulum (ER) stress (ERS) is involved in various cardiovascular diseases. Our previous study verified that ERS took part in the development of cardiac hypertrophy; however, its mechanism is still unclear. This study aimed to investigate the roles of the calcineurin (CaN) signal pathway in hypertrophy induced by the ERS inductor thapsigargin (TG) in neonatal cardiomyocytes from Sprague-Dawley rats. Investigation of ER chaperone expression, ER staining, and calreticulin immunofluorescence were used to detect the ERS response. mRNA expression of atrial natriuretic peptide and brain natriuretic peptide, total protein synthesis rate, and cell surface area were used to evaluate cardiac hypertrophy induced by TG. TG induced a significant ERS response along with hypertrophy in a dose- and time-dependent manner in cardiomyocytes, which was verified by treatment with tunicamycin, another ERS inducer. Furthermore, TG induced a significant elevation of the intracellular Ca(2+) level, CaN activation, and myocyte enhancer factor 2c (MEF2c) expression in a dose- and time-dependent manner in cardiomyocytes. Cyclosporine A, a CaN inhibitor, markedly suppressed MEF2c nuclear translocation and inhibited TG-induced hypertrophy. These results demonstrate that ERS induces cardiac hypertrophy and that the CaN-MEF2c pathway is involved in ERS-induced hypertrophy in cardiomyocytes.