Combined LXR and RXR Agonist Therapy Increases ABCA1 Protein Expression and Enhances ApoAI-Mediated Cholesterol Efflux in Cultured Endothelial Cells.
Combined LXR and RXR Agonist Therapy Increases ABCA1 Protein Expression and Enhances ApoAI-Mediated Cholesterol Efflux in Cultured Endothelial Cells.
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联合LXR和RXR激动剂治疗增加了ABCA1蛋白的表达，并增强了培养的内皮细胞中ApoaI介导的胆固醇外排。
DOI：
10.3390/metabo11090640
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发表时间：
2021-09-18
期刊：
影响因子：
4.1
通讯作者：
Stamatikos A
中科院分区：
文献类型：
--
作者：
Huang K;Jo H;Echesabal-Chen J;Stamatikos A
内皮细胞中ATP结合盒转运体A1（ABCA1）的表达可抵御动脉粥样硬化，这种抗动脉粥样硬化作用部分归因于其增强了载脂蛋白AI（apoAI）介导的胆固醇流出。ABCA1是肝脏X受体（LXR）和维甲酸X受体（RXR）的靶基因；因此，用LXR和/或RXR激动剂处理内皮细胞可能会增加ABCA1的表达。我们测试了用内源性LXR激动剂22（R）-羟基胆固醇、合成LXR激动剂GW3965、内源性RXR激动剂9-顺式视黄酸或合成RXR激动剂SR11237处理培养的永生化小鼠主动脉内皮细胞（iMAEC），是否会增加ABCA1蛋白的表达。我们观察到，单独用GW3965或SR11237处理iMAEC时，ABCA1蛋白表达显著增加，但单独用22（R）-羟基胆固醇或9-顺式视黄酸处理iMAEC时，未观察到ABCA1蛋白的显著增加。然而，当用22（R）-羟基胆固醇和9-顺式视黄酸的组合，或GW3965和SR11237的组合处理iMAEC时，我们观察到ABCA1蛋白表达和apoAI介导的胆固醇流出均显著增加。此外，基于血管细胞黏附分子-1（VCAM-1）、细胞间黏附分子-1（ICAM-1）、趋化因子配体2（CCL2）和白细胞介素-6（IL-6）的信使核糖核酸（mRNA）表达情况，用22（R）-羟基胆固醇和9-顺式视黄酸的组合，或GW3965和SR11237的组合处理iMAEC，不会引发炎症反应。基于我们的研究结果，将LXR和RXR激动剂精准递送至内皮细胞，可能是一种有前景的抗动脉粥样硬化方法。
Endothelial ABCA1 expression protects against atherosclerosis and this atheroprotective effect is partially attributed to enhancing apoAI-mediated cholesterol efflux. ABCA1 is a target gene for LXR and RXR; therefore, treating endothelial cells with LXR and/or RXR agonists may increase ABCA1 expression. We tested whether treating cultured immortalized mouse aortic endothelial cells (iMAEC) with the endogenous LXR agonist 22(R)-hydroxycholesterol, synthetic LXR agonist GW3965, endogenous RXR agonist 9-cis-retinoic acid, or synthetic RXR agonist SR11237 increases ABCA1 protein expression. We observed a significant increase in ABCA1 protein expression in iMAEC treated with either GW3965 or SR11237 alone, but no significant increase in ABCA1 protein was observed in iMAEC treated with either 22(R)-hydroxycholesterol or 9-cis-retionic acid alone. However, we observed significant increases in both ABCA1 protein expression and apoAI-mediated cholesterol efflux when iMAEC were treated with a combination of either 22(R)-hydroxycholesterol and 9-cis-retinoic acid or GW3965 and SR11237. Furthermore, treating iMAEC with either 22(R)-hydroxycholesterol and 9-cis-retinoic acid or GW3965 and SR11237 did not trigger an inflammatory response, based on VCAM-1, ICAM-1, CCL2, and IL-6 mRNA expression. Based on our findings, delivering LXR and RXR agonists precisely to endothelial cells may be a promising atheroprotective approach.
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DOI：
10.2183/pjab.86.484
发表时间：
2010
期刊：
Proceedings of the Japan Academy. Series B, Physical and biological sciences
影响因子：
--
作者：
Endo A
通讯作者：
Endo A
影响因子：
1.9
作者：
Esobi IC;Barksdale C;Heard-Tate C;Reigers Powell R;Bruce TF;Stamatikos A
通讯作者：
Stamatikos A
影响因子：
15.9
作者：
Ishikawa, Tomonori;Yuhanna, Ivan S.;Umetani, Michihisa
通讯作者：
Umetani, Michihisa
影响因子：
5.3
作者：
Kolseth, Ingrid B. M.;Agren, Joanna;Dahle, Maria K.
通讯作者：
Dahle, Maria K.
影响因子：
4.8
作者：
Cha, Ji-Young;Repa, Joyce J.
通讯作者：
Repa, Joyce J.