Blessing Erwin, Preusch Michael, Kranzhöfer Roger, Kinscherf Ralf, Marx Nikolaus, Rosenfeld Michael E, Isermann Berend, Weber Christian M, Kreuzer Jörg, Gräfe Julia, Katus Hugo A, Bea Florian
Medizinische Klinik III, Universität Heidelberg, Heidelberg, Germany.
Atherosclerosis. 2008 Aug;199(2):295-303. doi: 10.1016/j.atherosclerosis.2007.10.037. Epub 2008 Feb 21.
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 1 (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-1 (Egr-1) within the lesions. Electrophoretic mobility shift assays revealed reduced DNA-binding activity of nuclear factor kappaB (NFkappaB) 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 (PPARgamma). Target genes of PPARgamma, such as inducible nitric oxide synthase, NFkappaB and Egr-1, 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 NFkappaB and Egr-1 and through the activation of PPARgamma.
临床研究表明，使用血管紧张素转换酶（ACE）抑制剂或1型血管紧张素II受体（AT(1)）拮抗剂抑制肾素-血管紧张素系统（RAS）可降低心血管疾病风险。本研究的目的是比较AT(1)拮抗剂替米沙坦与ACE抑制剂雷米普利对晚期动脉粥样硬化病变的潜在作用机制。给60只表现出晚期动脉粥样硬化病变的32周龄载脂蛋白E缺乏小鼠喂食添加了雷米普利或替米沙坦的普通饲料，持续16周。另外20只小鼠喂食标准饲料。接受替米沙坦治疗的小鼠无名动脉内动脉粥样硬化病变大小进展减少了38%，接受雷米普利治疗的小鼠减少了18%。接受替米沙坦治疗的小鼠斑块内出血频率和坏死核心大小等斑块不稳定迹象减少。此外，替米沙坦治疗的小鼠病变内巨噬细胞较少，早期生长反应基因-1（Egr-1）表达降低。电泳迁移率变动分析显示，替米沙坦治疗的小鼠主动脉中核因子κB（NFκB）的DNA结合活性降低。对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（PPARγ）的启动子激活增强。替米沙坦预处理后，PPARγ的靶基因，如诱导型一氧化氮合酶、NFκB和Egr-1，活性降低。这些数据表明，替米沙坦对RAS的长期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，可能是通过降低促炎转录因子NFκB和Egr-1的活性以及激活PPARγ来实现的。
