Effect of inflammatory factor-induced cyclo-oxygenase expression on the development of reperfusion-related no-reflow phenomenon in acute myocardial infarction
Effect of inflammatory factor-induced cyclo-oxygenase expression on the development of reperfusion-related no-reflow phenomenon in acute myocardial infarction
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DOI：
10.1111/1440-1681.12339
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发表时间：
2015-02-01
影响因子：
2.9
通讯作者：
Zhang, Xingwei
中科院分区：
文献类型：
--
作者：
Jiao, Qibin;Ke, Qiang;Zhang, Xingwei
心肌梗死再灌注治疗后无复流是临床预后的一个强有力的预测指标。急性心肌梗死患者接受直接经皮冠状动脉介入治疗后，炎症因子水平升高，包括C反应蛋白(CRP)，可能会影响心肌血流灌注。然而，无复流现象在PCI术后炎症应激中增加的原因尚不清楚。本研究的目的是确定CRP对环氧合酶(COX)表达的影响及其在无复流现象发生中的作用及其分子机制。无复流患者血浆CRP和IL-6水平明显升高，提示炎症因子在无复流现象的发生发展中起重要作用。在模拟无复流现象的大鼠模型中，进一步评估了再灌注后所涉及的机制。与正常复流大鼠相比，无复流大鼠心肌组织中COX-1和COX-2的表达均显著升高。环氧合酶抑制剂吲哚美辛(5 mg/kg，i.p.)显著减少了无复流区。在另一系列实验中，用临床相关浓度(5-25g/mL)的CRP处理人冠状动脉内皮细胞(HCAEC)。C-反应蛋白以时间和浓度依赖的方式显著增加COX-1和COX-2水平。此外，在CRP(5、10、25g/mL)处理的HCAEC中，细胞外信号调节激酶(ERK)和Jun氨基末端激酶(JNK)被激活。此外，ERK抑制剂pd98059(30moL/L)和JNK抑制剂sp600125(10moL/L)可阻断CRP诱导的COX-1和COX-2的表达12h。综上所述，本研究结果提示，CRP可以通过增加COX-1和COX-2的表达来促进无复流现象的发生，而COX-1和COX-2的表达部分是通过ERK和JNK活性来调节的。
No reflow after reperfusion therapy for myocardial infarction is a strong predictor of clinical outcome. Increased levels of inflammatory factors, including C-reactive protein (CRP), in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) may affect myocardial perfusion. However, why the no-reflow phenomenon increases in inflammation stress after PCI is not clear. The aim of the present study was to determine the effects and molecular mechanisms underlying the effects of CRP on the expression of cyclo-oxygenase (COX) on the development of the no-reflow phenomenon. There was a significant increase in plasma levels of CRP and interleukin (IL)-6 in no-reflow patients, suggesting that inflammatory factors play an important role in the development of the no-reflow phenomenon. The mechanisms involved were further evaluated after reperfusion in a rat model mimicking the no-reflow phenomenon. Compared with normal reflow rats, there were significant increases in both COX-1 and COX-2 in cardiac tissue from no-reflow rats. The COX inhibitor indomethacin (5mg/kg, i.p.) significantly reduced the no-reflow area. In another series of experiments, human coronary artery endothelial cells (HCAEC) were treated with CRP at clinically relevant concentrations (5-25g/mL). C-Reactive protein significantly increased COX-1 and COX-2 levels in a time- and concentration-dependent manner. In addition, extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) were activated in CRP (5, 10, 25g/mL)-treated HCAEC cultures. Furthermore, the ERK inhibitor pd98059 (30mol/L) and the JNK inhibitor sp600125 (10mol/L) blocked CRP-induced COX-1 and COX-2 expression for 12h. Together, the findings of the present study suggest that CRP can promote the development of the no-reflow phenomenon by increasing COX-1 and COX-2 expression, which is regulated, in part, via ERK and JNK activity.