血管紧张素Ⅱ受体拮抗剂对自发性高血压大鼠的血管炎症抑制作用

Anti-inflammatory effect of angiotensin Ⅱ receptor blockers in spontaneous hypertensive rats:role of monocyte chemoattractant protein-1 and its receptor C-C motif chemokine receptor-2

目的观察血管紧张素Ⅱ受体拮抗剂(ARB)对自发性高血压大鼠血管炎性反应以及单核细胞趋化蛋白1(MCP-1)/趋化因子CC亚家族受体2(CCR2)途径的影响,探讨MCP-1/CCR2途径在自发性高血压血管炎性反应中的作用。方法自发性高血压大鼠(SHR)24只,随机分为高血压对照组(HC)、低剂量氯沙坦组(LL)、高剂量氯沙坦组(HL)和替米沙坦组(T组),正常血压大鼠(WKY)6只为正常对照组(NC)。每天1次灌胃给药:LL组氯沙坦5 mg/kg,HL组氯沙坦30 mg/kg,T组替米沙坦30 mg/kg,HC组及NC组等量蒸馏水。4周后处死动物,免疫组化检测大鼠胸主动脉壁巨噬细胞浸润(ED-1标记),反转录-聚合酶链反应(RT-PCR)检测心、肾、胸主动脉、循环血单个核细胞MCP-1、CCR2的表达,对外周血单个核细胞进行MCP-1的趋化功能实验,酶联免疫吸附法(ELISA)观察大鼠血清MCP-1水平。结果SHR组与WKY组相比,胸主动脉壁ED-1阳性细胞明显增多(P<0.01),心、肾、胸主动脉、循环血单个核细胞MCP-1 mRNA、CCR2 mRNA明显升高(均为P<0.01),外周血单个核细胞对MCP-1的趋化性明显升高(P<0.01),血清MCP-1水平升高(P<0.01)。不同剂量氯沙坦及替米沙坦均能有效抑制各组织和循环中MCP-1及CCR2的表达、外周血单个核细胞对MCP-1的趋化性以及胸主动脉壁ED-1阳性细胞数(与HC组相比,LL组、HL组及T组均为P<0.01),上述作用不依赖ARB的降压作用。结论ARB通过调节MCP-1/CCR2途径抑制血管炎性反应,此作用独立于其降压作用。

Objective To investigate the effect of various angiotensin Ⅱreceptor blockers （ARBs） on vascular inflammatory status in spontaneous hypertensive rats （SHRs） and the expressions of monocyte chemoattractant protein-1 （MCP-1）/C-C motif chemokine receptor-2 （CCR2）. Methods Twenty-four SHRs were treated with placebo （HC）, losartan （LL 5 mg/kg or HL 30 mg/kg） and telmisartan （T 30 mg/kg） for 4 weeks respectively （6 rats in each group）. Six Wistar Kyoto rats （WKYs） were used as normotensive controls （NC）. The number of macrophages infiltrated into thoracic aorta was labeled by ED-1 antibody. The expressions of MCP-1 and CCR2 in heart, kidney, thoracic aorta and mononuclear cells in peripheral circulation were determined by retro-transcriptase polymerase chain reaction （RT-PCR）. The chemotaxis ability of mononuclear cells in peripheral circulation to MCP-1 was neasyred by chemotaxis assay, the serum concentration of MCP-1 was measured by ELISA. Results Compared to HC group, blood pressure was not affected by LL but significantly reduced in HL and T group. Compared with NC Group, ED-1 positive macrophage numbers in thoracic aorta and the expressions of MCP-1 and CCR2 in heart, kidney, thoracic aorta and mononuclear cells in peripheral circulation were significantly increased （ all P 〈 0. 01 ）, the chemotaxis of mononuclear cells in peripheral circulation to MCP-1 was significantly enhanced （P 〈 0. 01 ）, and serum level of MCP-1 was significantly elevated in HC Group （ P 〈 0. 01 ）. These effects could be blocked by LL, HL and T treatments （ all P 〈 0. 01 ）. Conclusions Anti-inflammatory effects of ARBs in vessels are mediated by MCP-1/CCR2 pathways independenting of blood pressure-lowering effect.