Li Lang, Li Dong-Hua, Qu Nan, Wen Wei-Ming, Huang Wie-Qiang
Department of Cardiology, First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Cardiology. 2010;117(3):207-15. doi: 10.1159/000321713. Epub 2010 Dec 8.
Inflammation plays an important role in coronary microembolization (CME)-induced myocardial injury. The present study was designed to investigate the role of extracellular signal-regulated kinases 1/2 (ERK1/2) signaling pathway in regulating myocardial inflammation and cardiac function in a rat model of CME.
Sprague-Dawley rats were randomly divided into three groups: sham-operated group (sham group), CME group and PD98059 group (15 animals per group). CME was produced by injection of 42-μm microspheres into the left ventricle with occlusion of the ascending aorta. Rats in the PD98059 group were injected with PD98059, a specific ERK1/2 inhibitor, 30 min before the CME operation. Western blotting and immunohistochemistry analysis were used to determine the activation of ERK1/2. Echocardiography was employed to evaluate cardiac function. Hematoxylin-eosin staining was performed to assay myocardial inflammation. Expression of TNF-α mRNA was determined by RT-PCR analysis, and activity of NF-κB was assessed by electrophoretic mobility shift assay.
CME dramatically induced cardiac dysfunction (left ventricular ejection fraction, LVEF, was 72.97 ± 3.20% in the CME vs. 82.69 ± 3.50% in the sham group, p < 0.05) and local myocardial inflammatory response, both of which were ameliorated significantly by PD98059 (LVEF was 76.46 ± 4.46 and p < 0.05 vs. CME group). When compared to the CME group, PD98059 markedly attenuated the increased phosphorylation of ERK1/2 (0.48 ± 0.11 vs. 0.92 ± 0.10, p < 0.05), expression of TNF-α mRNA (0.42 ± 0.06 vs. 0.94 ± 0.04, p < 0.05) and activity of NF-κB (104.83 ± 13.65 vs. 540.79 ± 24.95, p < 0.05) in CME rat myocardium.
The present study demonstrates a novel role of the ERK1/2 signaling pathway in promoting myocardium inflammation and dysfunction in CME, and suggests that ERK1/2 is a novel potential therapeutic target for CME.
炎症在冠状动脉微栓塞（CME）诱导的心肌损伤中起重要作用。本研究旨在探讨细胞外信号调节激酶1/2（ERK1/2）信号通路在CME大鼠模型中调节心肌炎症和心脏功能的作用。
将Sprague-Dawley大鼠随机分为三组：假手术组（假手术组）、CME组和PD98059组（每组15只动物）。通过将42μm微球注入左心室并阻断升主动脉来产生CME。PD98059组大鼠在CME手术前30分钟注射特异性ERK1/2抑制剂PD98059。采用蛋白质免疫印迹法和免疫组织化学分析来测定ERK1/2的激活情况。采用超声心动图评估心脏功能。进行苏木精-伊红染色以检测心肌炎症。通过逆转录-聚合酶链反应（RT-PCR）分析测定肿瘤坏死因子-α（TNF-α）mRNA的表达，并通过电泳迁移率变动分析评估核因子-κB（NF-κB）的活性。
CME显著诱导心脏功能障碍（CME组左心室射血分数，LVEF，为72.97±3.20%，假手术组为82.69±3.50%，p<0.05）和局部心肌炎症反应，而PD98059均使其显著改善（LVEF为76.46±4.46，与CME组相比p<0.05）。与CME组相比，PD98059显著减弱了CME大鼠心肌中ERK1/2磷酸化的增加（0.48±0.11对0.92±0.10，p<0.05）、TNF-α mRNA的表达（0.42±0.06对0.94±0.04，p<0.05）和NF-κB的活性（104.83±13.65对540.79±24.95，p<0.05）。
本研究证明了ERK1/2信号通路在促进CME中的心肌炎症和功能障碍方面的新作用，并表明ERK1/2是CME的一个新的潜在治疗靶点。
