曲美他嗪对冠状动脉微栓塞中PDCD4/NF-κB/TNF-α信号通路的影响
Effects of Trimetazidine on PDCD4/NF-κB/TNF-α Pathway in Coronary Microembolization.
作者信息
Su Qiang, Li Lang, Zhao Jinmin, Sun Yuhan, Yang Huafeng
机构信息
Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Guangxi, China.
出版信息
Cell Physiol Biochem. 2017;42(2):753-760. doi: 10.1159/000478067. Epub 2017 Jun 19.
BACKGROUND/AIMS: The local inflammatory response caused by coronary microembolization (CME) is the primary cause of progressive cardiac dysfunction. The PDCD4/NF-κB/TNF-α signaling pathway plays a significant role in CME-induced myocardial Inflammation. Trimetazidine (TMZ) reduces myocardial injury, caused by percutaneous coronary intervention, through relieving the CME-induced myocardial systolic dysfunction. Therefore, the present study investigated the role of TMZ pre-treatment in the protection of myocardium after CME and PDCD4/NF-κB/TNF-α in mini pigs.
METHODS
20 Bama mini pigs were randomized into sham operation (sham), microembolization (CME), TMZ, and siRNA-PDCD4 groups (n = 5). The CME model was established by injecting polyethylene microspheres via microcatheter into the left anterior descending coronary artery. The TMZ group was injected 2.5 mg/kg drug via ear vein 30 min before CME; whereas, the siRNA-PDCD4 group was transfected with PDCD4 siRNA at the left anterior descending coronary artery via microcatheter 72h before CME. Cardiac function indexes were measured using cardiac echocardiography. The mRNA expression of PDCD4 and TNF-α in the myocardium was detected by quantitative fluorescence PCR, and the protein expression of PDCD4, NF-κB (p65), and TNF-α by Western blot.
RESULTS
Echocardiographic parameters showed lower cardiac function and higher serum cTnI level in the CME group than sham, which was manifested as reduced left ventricular ejection fraction (LVEF), left ventricular fractional shortening (FS), cardiac output (CO), and increased left ventricular diastolic diameter (LVEDd). Compared to the CME group, the CME-induced cardiac function injury was reduced, and the serum cTnI level was decreased in the TMZ and siRNA-PDCD4 groups. The expressions of PDCD4, NF-κB (p65), and TNF-α were significantly increased in the CME than the sham groups (P < 0.05), and significantly decreased in the TMZ and siRNA-PDCD4 groups than the CME group (P < 0.05).
CONCLUSION
TMZ pretreatment effectively reduced the myocardial damage caused by CME via inhibiting the PDCD4/NF-κB/ TNF-α pathway in cardiomyocytes.
背景/目的：冠状动脉微栓塞（CME）引起的局部炎症反应是进行性心功能障碍的主要原因。PDCD4/NF-κB/TNF-α信号通路在CME诱导的心肌炎症中起重要作用。曲美他嗪（TMZ）通过减轻CME诱导的心肌收缩功能障碍，减少经皮冠状动脉介入治疗引起的心肌损伤。因此，本研究探讨了TMZ预处理在小型猪CME后心肌保护及PDCD4/NF-κB/TNF-α中的作用。
方法
将20只巴马小型猪随机分为假手术组（sham）、微栓塞组（CME）、TMZ组和siRNA-PDCD4组（n = 5）。通过微导管将聚乙烯微球注入左前降支冠状动脉建立CME模型。TMZ组在CME前30分钟经耳静脉注射2.5mg/kg药物；而siRNA-PDCD4组在CME前72小时经微导管在左前降支冠状动脉转染PDCD4 siRNA。使用心脏超声心动图测量心功能指标。通过定量荧光PCR检测心肌中PDCD4和TNF-α的mRNA表达，通过蛋白质印迹法检测PDCD4、NF-κB（p65）和TNF-α的蛋白表达。
结果
超声心动图参数显示，CME组的心功能低于假手术组，血清cTnI水平高于假手术组，表现为左心室射血分数（LVEF）、左心室缩短分数（FS）、心输出量（CO）降低，左心室舒张直径（LVEDd）增加。与CME组相比，TMZ组和siRNA-PDCD4组CME诱导的心脏功能损伤减轻，血清cTnI水平降低。CME组中PDCD4、NF-κB（p65）和TNF-α的表达明显高于假手术组（P < 0.05），TMZ组和siRNA-PDCD4组中这些蛋白的表达明显低于CME组（P < 0.05）。
结论
TMZ预处理通过抑制心肌细胞中的PDCD4/NF-κB/TNF-α途径有效减轻了CME引起的心肌损伤。
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