Lalloyer Fanny, Fiévet Catherine, Lestavel Sophie, Torpier Gérard, van der Veen Jelske, Touche Véronique, Bultel Stéphanie, Yous Saïd, Kuipers Folkert, Paumelle Réjane, Fruchart Jean-Charles, Staels Bart, Tailleux Anne
Institut Pasteur de Lille, Département d'Athérosclérose, Lille, France.
Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2731-7. doi: 10.1161/01.ATV.0000248101.93488.84. Epub 2006 Sep 28.
The activity of the antitumoral agent bexarotene (Targretin, Bexarotene) depends on its binding to the nuclear retinoid-X receptor (RXR) and subsequent transcriptional regulation of target genes. Through RXR activation, bexarotene may modulate numerous metabolic pathways involved in atherosclerosis. Here, we investigated the effect of bexarotene on atherosclerosis progression in a dyslipidemic murine model, the human apolipoprotein E2 knockin mouse, that develops essentially macrophage-laden lesions.
Atherosclerotic lesions together with different metabolic pathways involved in atherosclerosis were investigated in mice treated or not with bexarotene. Bexarotene protects from atherosclerosis development in mice, at least in part by improving the circulating cholesterol distribution profile likely via a marked decrease of dietary cholesterol absorption caused by modulation of intestinal expression of genes recently identified as major players in this process, Niemann-Pick-C1-Like1 (NPC1L1) and CD13. This atheroprotection appears despite a strong hypertriglyceridemia. Moreover, bexarotene treatment only modestly modulates inflammatory gene expression in the vascular wall, but markedly enhanced the capacity of macrophages to efflux cellular lipids.
These data provide evidence of a favorable pharmacological effect of bexarotene on atherosclerosis despite the induction of hypertriglyceridemia, likely via a beneficial action on intestinal absorption and macrophage efflux.
抗肿瘤药物贝沙罗汀（他扎罗汀，Bexarotene）的活性取决于其与核视黄酸X受体（RXR）的结合以及随后对靶基因的转录调控。通过激活RXR，贝沙罗汀可能会调节参与动脉粥样硬化的众多代谢途径。在此，我们在一种血脂异常小鼠模型——人载脂蛋白E2基因敲入小鼠中研究了贝沙罗汀对动脉粥样硬化进展的影响，该模型主要形成富含巨噬细胞的病变。
在接受或未接受贝沙罗汀治疗的小鼠中，研究了动脉粥样硬化病变以及参与动脉粥样硬化的不同代谢途径。贝沙罗汀可保护小鼠免受动脉粥样硬化的发展，至少部分是通过改善循环胆固醇分布情况，这可能是通过调节最近被确定为该过程主要参与者的基因——尼曼-匹克C1样蛋白1（NPC1L1）和CD13在肠道的表达，从而显著降低膳食胆固醇吸收来实现的。尽管出现了严重的高甘油三酯血症，但这种抗动脉粥样硬化作用仍然存在。此外，贝沙罗汀治疗仅适度调节血管壁中的炎症基因表达，但显著增强了巨噬细胞排出细胞内脂质的能力。
这些数据提供了证据，表明尽管贝沙罗汀会诱导高甘油三酯血症，但它对动脉粥样硬化具有有益的药理作用，这可能是通过对肠道吸收和巨噬细胞脂质外流的有益作用实现的。
