Anti-atherosclerotic properties of telmisartan in advanced atherosclerotic lesions in apolipoprotein E deficient mice
Anti-atherosclerotic properties of telmisartan in advanced atherosclerotic lesions in apolipoprotein E deficient mice
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DOI：
10.1016/j.atherosclerosis.2007.10.037
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发表时间：
2008-08-01
期刊：
影响因子：
5.3
通讯作者：
Bea, Florian
中科院分区：
文献类型：
--
作者：
Blessing, Erwin;Preusch, Michael;Bea, Florian
临床研究表明，血管紧张素转换酶（ACE）抑制剂或血管紧张素II受体I型（AT（1））拮抗剂抑制肾素-血管紧张素系统（RAS）可减少心血管疾病。本研究的目的是评价与ACE抑制剂雷米普利相比，At（1）拮抗剂替米沙坦对晚期动脉粥样硬化病变的潜在机制。32周龄载脂蛋白E缺陷小鼠（n = 60）表现为晚期动脉粥样硬化病变，喂养饲料中添加雷米普利或替米沙坦16周。20只小鼠接受标准饮食。接受替米沙坦的小鼠和接受雷米普利的小鼠无名动脉内动脉粥样硬化病变大小的进展减少了38%和18%。接受替米沙坦的小鼠中斑块不稳定的体征，如斑块内出血的频率和坏死核心的大小减少。此外，替米沙坦治疗小鼠的巨噬细胞减少，病变内早期生长反应基因-I（Egr-I）的表达降低。电泳迁移率改变试验显示，替米沙坦处理小鼠主动脉中核因子κ B（NF κ B）的DNA结合活性降低。小鼠巨噬细胞的体外研究表明，核转录因子过氧化物酶体增殖物激活受体γ（PPAR γ）的启动子激活增强。PPAR γ的靶基因，如诱导型一氧化氮合酶、NF κ B B和Egr-I，在替米沙坦预处理后活性降低，这些数据表明，替米沙坦对RAS的慢性抑制在减少晚期动脉粥样硬化和促进斑块稳定性方面优于雷米普利，这可能是通过降低促炎转录因子NF κ B B和Egr-I的活性以及通过激活PPAR γ实现的。(C)2007爱思唯尔爱尔兰有限公司保留所有权利。
Clinical studies have demonstrated that the inhibition of the renin-angiotensin system (RAS) by either an angiotensin-converting enzyme (ACE)-inhibitor or an angiotensin II receptor type I (AT(1))-antagonist reduces cardiovascular disease. The objective of this study was to evaluate underlying mechanisms of the At(1)-antagonist telmisartan in comparison to the ACE-inhibitor ramipril on advanced atherosclerotic lesions.Thirty-two-week-old apolipoprotein E deficient mice (n = 60) exhibiting advanced atherosclerotic lesions were fed a chow diet supplemented with ramipril or telmisartan for 16 weeks. Twenty mice received a standard diet. Mice receiving telmisartan had a 38% and mice receiving ramipril had a 18% reduction in progression of atherosclerotic lesion size within the innominate artery. Signs of plaque instability such as frequency of intra-plaque hemorrhage and size of the necrotic cores were reduced in mice receiving telmisartan. Furthermore, telmisartan-treated mice had fewer macrophages and reduced expression of early growth response gene-I (Egr-I) within the lesions. Electrophoretic mobility shift assays revealed reduced DNA-binding activity of nuclear factor kappa B (NF kappa B) in the aorta of telmisartan-treated mice. In vitro studies in mouse macrophages demonstrated enhanced promoter activation of the nuclear transcription factor peroxisome proliferators-activated receptor gamma (PPAR gamma). Target genes of PPAR gamma, such as inducible nitric oxide synthase, NF kappa B and Egr-I, showed reduced activity after telmisartan pretreatment.These data suggest that chronic inhibition of the RAS by telmisartan prevails in reducing advanced atherosclerosis and promoting plaque stability over ramipril, possibly through the reduced activity of the pro-inflammatory transcription factors NF kappa B and Egr-I and through the activation of PPAR gamma. (C) 2007 Elsevier Ireland Ltd. All rights reserved.