Bertrand-Thiebault Céline, Masson Christine, Siest Gérard, Batt Anne-Marie, Visvikis-Siest Sophie
INSERM, U525, Equipe 4, Univ Henri Poincaré, Nancy I, Nancy, F-54000 France.
J Cardiovasc Pharmacol. 2007 May;49(5):306-15. doi: 10.1097/FJC.0b013e31803e8756.
Endothelial cells and smooth muscle cells are the major cells that constitute blood vessels, and endothelial cells line the lumen of blood vessels. These 2 types of cells also play an integral role in the regional specialization of vascular structure. On the basis of these observations, we designed our study to investigate the effect of various statins on CYP expression in endothelial cells. 3-hydroxymethyl coenzyme A reductase inhibitors play an important role in vascular function. The majority of the statins available on the market show extensive metabolism by cytochrome P450 (CYP) enzymes. Both cell types are involved in the bioconversion of arachidonic acid into vasoactive compounds. The aim of this study was to demonstrate the effect of statins on cytochrome P450 expression in endothelial cells. Our results show that endothelial cells expressed both CYPs involved in epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs) production and the nuclear receptor implicated in cytochrome P450 regulation. Treatment of endothelial cells with lovastatin increased CYP2C9 expression. After 96 hours of treatment, fluvastatin and lovastatin clearly increased CYP2C9 protein level. CAR but not PXR was expressed in endothelial cells, indicating that the upregulating effect of statins on CYP2C9 in endothelial cells could be mediated through CAR only due to the lack of expression of PXR in these cells.
内皮细胞和平滑肌细胞是构成血管的主要细胞，内皮细胞排列在血管腔内。这两种类型的细胞在血管结构的区域特化中也起着不可或缺的作用。基于这些观察结果，我们设计了本研究来调查各种他汀类药物对内皮细胞中细胞色素P450（CYP）表达的影响。3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂在血管功能中起重要作用。市场上大多数可用的他汀类药物都显示出被细胞色素P450（CYP）酶广泛代谢。这两种细胞类型都参与了花生四烯酸向血管活性化合物的生物转化。本研究的目的是证明他汀类药物对内皮细胞中细胞色素P450表达的影响。我们的结果表明，内皮细胞表达了参与环氧二十碳三烯酸（EETs）和羟基二十碳四烯酸（HETEs）生成的两种CYPs以及参与细胞色素P450调节的核受体。用洛伐他汀处理内皮细胞可增加CYP2C9的表达。处理96小时后，氟伐他汀和洛伐他汀明显增加了CYP2C9蛋白水平。内皮细胞中表达了CAR但未表达PXR，这表明他汀类药物对内皮细胞中CYP2C9的上调作用可能仅通过CAR介导，因为这些细胞中缺乏PXR的表达。
