ACE inhibition lowers angiotensin II-induced chemokine expression by reduction of NF-κB activity and AT1 receptor expression
ACE inhibition lowers angiotensin II-induced chemokine expression by reduction of NF-κB activity and AT1 receptor expression
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DOI：
10.1016/j.bbrc.2004.10.059
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发表时间：
2004-12-10
影响因子：
3.1
通讯作者：
Garlichs, CD
中科院分区：
文献类型：
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作者：
Schmeisser, A;Soehnlein, O;Garlichs, CD
Objective.血管紧张素转换酶（ACE）抑制剂可显著改善动脉粥样硬化患者的生存率。虽然ACE抑制剂减少局部血管紧张素II（AngII）的形成，丝氨酸蛋白酶形成AngII的巨大数量独立于ACE。因此，我们的研究集中在ACE抑制剂雷米普利拉对趋化因子释放，血管紧张素Ⅱ受体（ATR）的表达，和NF-κ B活性与血管紧张素Ⅱ刺激单核细胞的影响。血管紧张素II诱导的单核细胞中IL-8和MCP-1蛋白和RNA的上调被AT 1 R阻断剂氯沙坦抑制，但不被AT 2 R阻断剂PD 123.319抑制。雷米普利拉剂量依赖性地抑制AngII诱导的IL-8和MCP-1的上调。雷米普利拉对AngII诱导的趋化因子产生和释放的抑制作用部分是由于NF-κ B的下调，但更多的是由于单核细胞和内皮细胞中AT 1受体的选择性和高度显著的表达减少。在我们的研究中，我们首次证明了雷米普利拉降低单核细胞和内皮细胞中AT 1 R的表达。此外，雷米普利拉下调NF-κ B活性，从而减少了AngII诱导的单核细胞中IL-8和MCP-1的释放。这种抑制作用，至少部分地，可能有助于ACE抑制剂在治疗冠状动脉疾病中的临床获益。(C)2004年爱思唯尔公司All rights reserved.
Objective. Angiotensin converting enzyme (ACE) inhibitors significantly improve survival in patients with atherosclerosis. Although ACE inhibitors reduce local angiotensin II (AngII) formation, serine proteases form AngII to an enormous amount independently from ACE. Therefore, our study concentrates on the effect of the ACE-inhibitor ramiprilat on chemokine release, AngII receptor (ATR) expression, and NF-kappaB activity in monocytes stimulated with AngII.Methods and results. AngII-induced upregulation of IL-8 and MCP-1 protein and RNA in monocytes was inhibited by the AT1R-blocker losartan, but not by the AT2R-blocker PD 123.319. Ramiprilat dose-dependently suppressed AngII-induced upregulation of IL-8 and MCP-1. The suppressive effect of ramiprilat on AngII-induced chemokine production and release was in part caused by downregulation of NF-kappaB, but more by a selective and highly significant reduced expression of AT1 receptors as shown in monocytes and endothelial cells.Conclusion. In our study we demonstrated for the first time that ramiprilat reduced expression of AT1R in monocytes and endothelial cells. In addition, ramiprilat downregulated NF-kappaB activity and thereby reduced the AngII-induced release of IL-8 and MCP-1 in monocytes. This antiinflammatory effect, at least in part, may contribute to the clinical benefit of the ACE inhibitor in the treatment of coronary artery disease. (C) 2004 Elsevier Inc. All rights reserved.