Pharmacological activation of the prostaglandin E2 receptor EP4 improves cardiac function after myocardial ischaemia/reperfusion injury
Pharmacological activation of the prostaglandin E2 receptor EP4 improves cardiac function after myocardial ischaemia/reperfusion injury
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DOI：
10.1093/cvr/cvn254
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发表时间：
2009-01-01
影响因子：
10.8
通讯作者：
Isobe, Mitsuaki
中科院分区：
文献类型：
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作者：
Hishikari, Keiichi;Suzuki, Jun-ichi;Isobe, Mitsuaki
前列腺素E-2受体(EP1-4)的几种亚型在临床和实验性心肌缺血/再灌注(I/R)损伤中表达增加。然而，它们在I/R中的病理生理学意义仍不清楚。因此，我们确定前列腺素受体EP4的激活是否抑制心肌I/R损伤。为了分析EP4的作用，我们给大鼠心肌I/R损伤后给予EP4选择性激动剂(EP4RAG，1或3 mg/kg)或赋形剂。再灌流7d后，I/R大鼠左室扩张、收缩功能障碍，心肌细胞肥大，间质纤维化。与赋形剂相比，EP4RAG显著减少了梗塞面积/缺血心肌(72.4+/-0.7vs.23.3+/-0.6%；P<；0.05)，并改善了左心室的收缩和扩张。EP4RAG还可减轻炎症细胞，特别是巨噬细胞的募集，并减轻心脏间质纤维化。单核细胞趋化蛋白(MCP)-1等细胞因子在非缺血区(ANAR)和缺血区(AAR)心肌中均升高，但Western印迹分析和核糖核酸酶保护实验显示EP4RAG抑制了这些变化。明胶酶谱显示EP4RAG显著降低ANAR和AAR中基质金属蛋白酶-2和-9的活性。趋化活性分析显示EP4RAG可抑制细胞因子刺激的巨噬细胞迁移，减少巨噬细胞培养上清液中单核细胞趋化蛋白-1的产生(587.3+/-55.3vs.171.5+/-47.5pg/mL；P<；0.05)。提示EP4激动剂通过抑制单核细胞趋化蛋白-1和炎性细胞，尤其是巨噬细胞的浸润，有效地减轻I/R损伤。
Increased expression of several subtypes of prostaglandin E-2 receptors (EP1-4) has recently been described in clinical and experimental myocardial ischaemia/reperfusion (I/R) injury. However, their pathophysiological significance in I/R remains obscure. Thus, we determined whether the activation of the prostanoid receptor, EP4, suppresses myocardial I/R injury.To analyse the role of EP4, we administered an EP4 selective agonist (EP4RAG, 1 or 3 mg/kg) or vehicle to rats with myocardial I/R injury. After 7 days of reperfusion, I/R rats exhibited left ventricular (LV) dilatation and contractile dysfunction with myocyte hypertrophy and interstitial fibrosis. EP4RAG significantly reduced infarction area/ischaemic myocardium (72.4 +/- 0.7 vs. 23.3 +/- 0.6%; P < 0.05) and improved LV contraction and dilatation compared with that of the vehicle. EP4RAG also attenuated the recruitment of inflammatory cells, especially macrophages, and interstitial fibrosis in hearts. Monocyte chemoattractant protein (MCP)-1 and other cytokines were increased in both non-ischaemic (area not at risk, ANAR) and ischaemic (area at risk, AAR) myocardium; however, western blot analysis and RNase protection assay showed that EP4RAG suppressed these changes. Gelatin zymography revealed EP4RAG significantly reduced matrix metalloproteinase-2 and -9 activities in both ANAR and AAR. Chemoattractant assay demonstrated that EP4RAG suppressed the migration of cytokine-stimulated macrophages and decreased the level of MCP-1 production in the supernatant (587.3 +/- 55.3 vs. 171.5 +/- 47.5 pg/mL; P < 0.05).The data suggest that the EP4 agonist is effective for attenuation of I/R injury by suppressing MCP-1 and the infiltration of inflammatory cells, especially macrophages.