Statins upregulate CD36 expression in human monocytes, an effect strengthened when combined with PPAR-γ ligands -: Putative contribution of Rho GTPases in statin-induced CD36 expression
Statins upregulate CD36 expression in human monocytes, an effect strengthened when combined with PPAR-γ ligands -: Putative contribution of Rho GTPases in statin-induced CD36 expression
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DOI：
10.1016/j.bcp.2003.09.006
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发表时间：
2004-01-15
影响因子：
5.8
通讯作者：
Vega, MA
中科院分区：
文献类型：
--
作者：
Ruiz-Velasco, N;Domínguez, A;Vega, MA
清道夫受体CD36在动脉粥样硬化、炎症、血栓形成和血管生成中发挥重要作用。他汀类药物除了降低血清胆固醇水平外，还对炎症、凝血和动脉粥样硬化病变稳定性具有多种作用。 PPAR-γ 配体影响巨噬细胞对许多炎症刺激的反应。在此，我们在人单核细胞中研究了他汀类药物单独使用以及与 PPAR-γ 配体联合使用对 CD36 表达的影响，以及他汀类药物调节作用的分子机制。我们的结果表明，他汀类药物通过增强 CD36 基因的转录来上调 CD36 表面蛋白和 mRNA。此外，他汀类药物和 PPAR-γ 配体的组合对 CD36 表达具有累加效应。甲羟戊酸和香叶基香叶醇可阻止他汀类药物对 CD36 表达的影响，表明香叶基香叶基化蛋白对 CD36 的调节是必需的。 Rho GTPases 抑制剂 C3 外切酶再现了他汀类药物的作用，而 Rho 激活剂溶血磷脂酸则下调 CD36。 RhoA 和 RhoB 显性失活突变体的瞬时表达诱导 CD36 启动子活性显着增加。最后，肌动蛋白细胞骨架破坏剂细胞松弛素 D 上调 CD36。这些数据表明，Rho 蛋白是 CD36 表达的重要调节剂，并强烈表明他汀类药物通过灭活 Rho GTPases 来破坏细胞骨架组织，从而增加 CD36 的表达。这些特征促使我们研究 Rho GTPases 和肌动蛋白细胞骨架调节剂对受他汀类药物影响的单核细胞功能的作用。 (C) 2003 Elsevier Inc. 保留所有权利。
Scavenger receptor CD36 plays important roles in atherosclerosis, inflammation, thrombosis, and angiogenesis. Statins besides lowering serum cholesterol levels, exhibit a variety of effects on inflammation, coagulation and atherosclerosis lesion stability. PPAR-gamma ligands influence macrophage responses to many inflammatory stimuli. Herein, we investigated in human monocytes the effect of statins alone, and in combination with PPAR-gamma ligands on CD36 expression, as well as the molecular mechanisms underlying the regulatory action of statins. Our results demonstrate that statins upregulate both CD36 surface protein and mRNA by potentiating the transcription of the CD36 gene. Furthermore, the combination of statins and PPAR-gamma ligands has an additive effect on CD36 expression. Effects of statins on CD36 expression were prevented by mevalonate and geranylgeraniol, indicating the requirement of geranylgeranylated proteins for CD36 regulation. Rho GTPases inhibitor C3 exoenzyme reproduced the effect of statins, while Rho activator lysophosphatidic acid downregulated CD36. Transient expression of dominant-negative mutants of RhoA and RhoB induced a significant increased in CD36 promoter activity. Finally, the actin cytoskeleton disrupter cytochalasin D upregulated CD36. These data indicate that Rho proteins are important modulators of CD36 expression, and strongly suggest that statins increased CD36 expression by disrupting cytoskeleton organization by inactivating Rho GTPases. These features prompt to investigate the roles of Rho GTPases and actin cytoskeleton modulators on monocytic functions affected by statins. (C) 2003 Elsevier Inc. All rights reserved.