Cross-talk between dyslipidemia and renin-angiotensin system and the role of LOX-1 and MAPK in atherogenesis - Studies with the combined use of rosuvastatin and candesartan
Cross-talk between dyslipidemia and renin-angiotensin system and the role of LOX-1 and MAPK in atherogenesis - Studies with the combined use of rosuvastatin and candesartan
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DOI：
10.1016/j.atherosclerosis.2005.04.016
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发表时间：
2006-02-01
期刊：
影响因子：
5.3
通讯作者：
Mehta, JL
中科院分区：
文献类型：
--
作者：
Chen, JW;Li, DY;Mehta, JL
越来越多的证据表明，血脂异常与肾素-血管紧张素系统（RAS）在动脉粥样硬化形成中存在相互作用。血脂异常和RAS激活都增强了一种新描述的氧化低密度脂蛋白（ox-LDL）受体，凝集素样ox-LDL受体-1（LOX-1）的表达。我们推测，瑞舒伐他汀（一种3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂）和坎地沙坦（一种血管紧张素11 I型受体阻滞剂）对RAS的血脂异常阻断作用，对LOX-1表达和动脉粥样硬化形成具有协同抑制作用。Apo-E基因敲除小鼠单独喂食高胆固醇饮食（1%胆固醇，HC-饮食），或HC-饮食与瑞舒伐他汀（1 mg/（kg d））、坎地沙坦（1 mg/（kg d））或两者。12周后，通过苏丹IV染色确定动脉粥样硬化的程度。Apo-E基因敲除小鼠在HC-饮食有广泛的动脉粥样硬化。瑞舒伐他汀和坎地沙坦均可降低动脉粥样硬化程度（分别降低23%和26%），尽管采用HC饮食;然而，瑞舒伐他汀和坎地沙坦联合用药可进一步降低动脉粥样硬化程度（降低67%）。瑞舒伐他汀使血浆总胆固醇水平降低50%以上，而坎地沙坦无影响。LOX-1蛋白表达被发现在HC饮食喂养的apo-E基因敲除小鼠中显著上调。虽然瑞舒伐他汀和坎地沙坦对动脉粥样硬化组织中LOX-1的表达均具有较小的抑制作用，但联合用药完全阻断LOX-1的上调。在apo-E基因敲除小鼠中，P38丝裂原活化蛋白激酶（MAPK）表达和磷酸化增加，单独使用瑞舒伐他汀或坎地沙坦可减弱，两种药物联合使用可完全阻断。HC-饮食、瑞舒伐他汀、坎地沙坦或其组合不影响P44/42 MAPK表达和磷酸化。本研究证明了瑞舒伐他汀和坎地沙坦对动脉粥样硬化形成以及LOX-1表达和p38 MAPK激活的有效作用，但对p44/42 MAPK无影响。(c)2005爱思唯尔爱尔兰有限公司保留所有权利。
There is increasing evidence of cross-talk between dyslipidemia and renin-angiotensin system (RAS) in atherogenesis. Both dyslipidemia and RAS activation enhance the expression of a newly described receptor for oxidized-low density lipoprotein (ox-LDL), lectin-like ox-LDL receptor-1 (LOX-1). We postulated that the blockade of dyslipidemia with rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and RAS with candesartan, an angiotensin 11 type I receptor blocker, would have a synergistic inhibitory effect on LOX-1 expression and atherogenesis. Apo-E knockout mice were fed a high-cholesterol diet (1% cholesterol, HC-diet) alone, or HC-diet with rosuvastatin (1 mg/(kg d)), candesartan (I mg/(kg d)) or with both. Twelve weeks later the extent of atherosclerosis was determined by Sudan IV staining. Apo-E knockout mice on HC-diet had extensive atherosclerosis. Both rosuvastatin and candesartan decreased the extent of atherosclerosis (by 23 and 26%, respectively), despite the HC-diet; however, the combination of rosuvastatin and candesartan reduced atherosclerosis further (by 67%). Rosuvastatin decreased plasma levels of total cholesterol by over 50%, whereas candesartan had no effect. LOX-1 protein expression was found to be markedly up-regulated in HC-diet-fed apo-E knockout mice. While rosuvastatin and candesartan each had a small inhibitory effect on the expression of LOX-1 in the atherosclerotic tissues, the combination totally blocked the up-regulation of LOX-1. P38 mitogen-activated protein kinase (MAPK) expression and phosphorylation were increased in apo-E knockout mice, attenuated by rosuvastatin or candesartan alone, and completely blocked by the combination of the two agents. P44/42 MAPK expression and phosphorylation were not affected by the HC-diet, rosuvastatin, candesartan, or their combination. This study demonstrates the potent effect of rosuvastatin and candesartan on atherogenesis, as well as on the expression of LOX-1 and on the activation of p38 MAPK, but not p44/42 MAPK. (c) 2005 Elsevier Ireland Ltd. All rights reserved.