Differential ERK1/2 Signaling and Hypertrophic Response to Endothelin-1 in Cardiomyocytes from SHR and Wistar-Kyoto Rats: A Potential Target for Combination Therapy of Hypertension.
Differential ERK1/2 Signaling and Hypertrophic Response to Endothelin-1 in Cardiomyocytes from SHR and Wistar-Kyoto Rats: A Potential Target for Combination Therapy of Hypertension.
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DOI：
10.2174/1570161112666141014150007
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发表时间：
2015
影响因子：
4.5
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Zhu LA;Fang NY;Gao PJ;Jin X;Wang HY;Liu Z
细胞外信号调节激酶1/2（ERK 1/2）信号传导对内皮素-1（ET-1）诱导的心肌细胞肥大至关重要。本研究旨在探讨自发性高血压大鼠（SHR）和正常血压Wistar-Kyoto大鼠（WKY）心肌细胞（CMs）对ET-1刺激的肥大反应及ERK 1/2信号通路。原代新生SHR和WKY CM暴露于ET-1长达24小时。WKY CM中存在最小的基础ERK 1/2磷酸化，而SHR CM中观察到显著的基线ERK 1/2磷酸化。ET-1诱导SHR和WKY CM中ERK 1/2磷酸化呈时间和剂量依赖性增加。然而，ET-1诱导的ERK 1/2激活在SHR CM中比在WKY CM中发生得更早，磷酸化峰值水平显著更高，并且持续升高的时间更长。ET-1诱导的肥大反应在SHR CM中比在WKY CM中更突出，反映在增加的细胞表面积，细胞内肌动蛋白密度和蛋白质合成。用ERK 1/2磷酸化抑制剂PD 98059预处理可完全阻止ET-1诱导的SHR和WKY CM细胞ERK 1/2磷酸化以及细胞表面积和蛋白质合成的增加。特异性PI 3激酶抑制剂LY 294002可阻断ET-1诱导的Akt和ERK 1/2磷酸化及CMs蛋白质合成。这些数据表明，ERK 1/2信号在CM中差异增强，并且与SHR对ET-1的心脏肥大反应增加有关。在SHR和WKY中，ET-1诱导的ERK 1/2激活和心肌肥厚似乎是通过PI 3激酶/Akt信号转导介导的。ET-1对SHR CM细胞ERK 1/2的激活可能是联合治疗高血压的潜在靶点。
Extracellular signal regulated kinase½ (ERK1/2) signaling is critical to endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. This study was to investigate ERK1/2 signaling and hypertrophic response to ET-1 stimulation in cardiomyocytes (CMs) from spontaneous hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Primary neonatal SHR and WKY CMs were exposed to ET-1 for up to 24 hrs. Minimal basal ERK1/2 phosphorylation was present in WKY CMs, while a significant baseline ERK1/2 phosphorylation was observed in SHR CMs. ET-1 induced a time- and dose-dependent increase in ERK1/2 phosphorylation in both SHR and WKY CMs. However, ET-1-induced ERK1/2 activation occurred much earlier with significantly higher peak phosphorylation level, and stayed elevated for longer duration in SHR CMs than that in WKY CMs. ET-1-induced hypertrophic response was more prominent in SHR CMs than that in WKY CMs as reflected by increased cell surface area, intracellular actin density, and protein synthesis. Pre-treatment with ERK1/2 phosphorylation inhibitor PD98059 completely prevented ET-1-induced ERK1/2 phosphorylation and increases in cell surface area and protein synthesis in SHR and WKY CMs. The specific PI3 kinase inhibitor LY294002 blocked ET-1-induced Akt and ERK1/2 phosphorylation, and protein synthesis in CMs. These data indicated that ERK1/2 signaling was differentially enhanced in CMs, and was associated with increased cardiac hypertrophic response to ET-1 in SHR. ET-1-induced ERK1/2 activation and cardiac hypertrophy appeared to be mediated via PI3 kinase/Akt signaling in SHR and WKY. The differential ERK1/2 activation in SHR CMs by ET-1 might represent a potential target for combination therapy of hypertension.