Telmisartan inhibits CD4-positive lymphocyte migration independent of the angiotensin type 1 receptor via peroxisome proliferator-activated receptor-γ
Telmisartan inhibits CD4-positive lymphocyte migration independent of the angiotensin type 1 receptor via peroxisome proliferator-activated receptor-γ
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DOI：
10.1161/hypertensionaha.107.099028
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发表时间：
2008-02-01
期刊：
影响因子：
8.3
通讯作者：
Marx, Nikolaus
中科院分区：
文献类型：
--
作者：
Walcher, Daniel;Hess, Katharina;Marx, Nikolaus
CD4 阳性淋巴细胞迁移至血管壁是早期动脉粥样硬化形成的重要一步。 Telmisartan 是一种血管紧张素 1 型受体 (AT1R) 阻滞剂，具有过氧化物酶体增殖物激活受体 (PPAR)-γ 激活特性。本研究探讨了替米沙坦对 CD4 阳性细胞迁移的影响以及 PPAR γ 在此背景下的作用。 CD4 阳性淋巴细胞表达 AT1R 和 PPAR gamma。用基质细胞衍生因子 (SDF)-1 刺激 CD4 阳性淋巴细胞可导致细胞迁移增加 4.1 +/- 3.1 倍。用替米沙坦预处理细胞会以浓度依赖性方式降低这种效应，在替米沙坦浓度为 10 μmol/L 时，诱导作用最大可降低 1.6 +/- 0.7 倍（与 SDF-1 处理的细胞相比，P < 0.01；n = 22）。三种不同的 PPAR γ 激活剂罗格列酮、吡格列酮和 GW1929 具有相似的作用，而依普罗沙坦（一种非 PPAR γ 激活 AT1R 阻滞剂）不影响趋化因子诱导的淋巴细胞迁移。替米沙坦对 CD4 阳性淋巴细胞迁移的影响是通过早期抑制趋化因子诱导的磷脂酰肌醇 3 激酶活性来介导的。下游，替米沙坦抑制 F-肌动蛋白形成以及细胞间粘附分子 3 易位。用PPARγ小干扰RNA转染CD4阳性淋巴细胞消除了替米沙坦对迁移的影响，而阻断AT1R则没有这种效果。 Telmisartan 通过 PPAR gamma 抑制趋化因子诱导的 CD4 阳性细胞迁移，不依赖于 AT1R。这些数据提供了一种新的机制来解释替米沙坦如何通过其 PPAR γ 激活特性来调节淋巴细胞激活。
Migration of CD4-positive lymphocytes into the vessel wall represents an important step in early atherogenesis. Telmisartan is an angiotensin type 1 receptor ( AT1R) blocker with peroxisome proliferator-activated receptor ( PPAR)-gamma- activating properties. The present study examined the effect of telmisartan on CD4-positive cell migration and the role of PPAR gamma in this context. CD4-positive lymphocytes express both the AT1R and PPAR gamma. Stimulation of CD4-positive lymphocytes with stromal cell-derived factor ( SDF)-1 leads to a 4.1 +/- 3.1-fold increase in cell migration. Pretreatment of cells with telmisartan reduces this effect in a concentration-dependent manner to a maximal 1.6 +/- 0.7-fold induction at 10 mu mol/ L of telmisartan ( P < 0.01 compared with SDF-1 - treated cells; n = 22). Three different PPAR gamma activators, rosiglitazone, pioglitazone, and GW1929, had similar effects, whereas eprosartan, a non-PPAR gamma - activating AT1R blocker, did not affect chemokine-induced lymphocyte migration. Telmisartan's effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced phosphatidylinositol 3-kinase activity. Downstream, telmisartan inhibited F-actin formation, as well as intercellular adhesion molecule-3 translocation. Transfection of CD4-positive lymphocytes with PPAR gamma small interfering RNA abolished telmisartan's effect on migration, whereas blockade of the AT1R had no such effect. Telmisartan inhibits chemokine-induced CD4-positive cell migration independent of the AT1R via PPAR gamma. These data provide a novel mechanism to explain how telmisartan modulates lymphocyte activation by its PPAR gamma-activating properties.