Department of Pathophysiology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China.
Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1499-509. doi: 10.1152/ajpheart.00980.2009. Epub 2010 Mar 5.
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.
内质网应激（ERS）参与多种心血管疾病。我们之前的研究证实 ERS 参与了心肌肥厚的发展；然而，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 thapsigargin（TG）诱导的新生大鼠心肌细胞肥大中的作用。通过检测内质网伴侣表达、内质网染色和钙网蛋白免疫荧光来检测 ERS 反应。心房利钠肽和脑利钠肽的 mRNA 表达、总蛋白合成率和细胞表面积用于评估 TG 诱导的心肌肥厚。TG 在心肌细胞中以剂量和时间依赖的方式诱导显著的 ERS 反应和肥大，这通过另一种 ERS 诱导剂衣霉素的处理得到验证。此外，TG 在心肌细胞中以剂量和时间依赖的方式诱导细胞内 Ca(2+)水平、CaN 激活和肌细胞增强因子 2c（MEF2c）表达的显著升高。钙调神经磷酸酶抑制剂环孢菌素 A 显著抑制 MEF2c 核易位并抑制 TG 诱导的肥大。这些结果表明 ERS 诱导心肌肥厚，CaN-MEF2c 途径参与了心肌细胞中 ERS 诱导的肥大。
