Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang 330006, China.
Int J Mol Sci. 2023 Mar 21;24(6):5939. doi: 10.3390/ijms24065939.
Endothelial dysfunction (ED) is the initiation of atherosclerosis (AS). Our previous studies have found that cholesterol metabolism and the Wnt/β-catenin pathway can affect endoplasmic reticulum stress (ER stress), which ultimately leads to ED. However, the effects of cholesterol efflux on ED, which are caused by oxidative stress and the correlation among ER stress, Wnt/β-catenin pathway, and cholesterol efflux, are not clear during ED. To uncover them, the expressions of liver X receptors (LXRα and LXRβ) and ATP-binding cassette protein A1 (ABCA1) and G1 (ABCG1) in HUVECs (human umbilical vein endothelial cells) were measured under oxidative stress. Moreover, HUVECs were treated with LXR-623 (LXR agonist), cholesterol, tunicamycin, and salinomycin alone or together. The results indicated that oxidative stress-induced ED could deregulate the expressions of LXRα and LXRβ and trigger the ER stress and Wnt/β-catenin pathway, resulting thereafter in the accumulation of cholesterol. Furthermore, similar results were shown after treatment with cholesterol; however, the activation of liver X receptor (LXR) could reverse these changes. Furthermore, other results demonstrated that tunicamycin-induced ER stress could stimulate the accumulation of cholesterol and the Wnt/β-catenin pathway, further leading to ED. Inversely, salinomycin could reverse the above effects by deregulating the Wnt/β-catenin pathway. Collectively, our results showed that cholesterol efflux is partly responsible for the oxidative stress-induced ED; in addition, ER stress, the Wnt/β-catenin pathway, and cholesterol metabolism can interact with each other to promote ED.
内皮功能障碍（ED）是动脉粥样硬化（AS）的起始。我们之前的研究发现胆固醇代谢和 Wnt/β-连环蛋白通路可以影响内质网应激（ER 应激），这最终导致 ED。然而，胆固醇外排对 ED 的影响，以及 ER 应激、Wnt/β-连环蛋白通路和胆固醇外排之间的相关性，在 ED 期间并不清楚。为了揭示这些问题，我们在氧化应激下测量了 HUVECs（人脐静脉内皮细胞）中肝 X 受体（LXRα 和 LXRβ）和 ATP 结合盒蛋白 A1（ABCA1）和 G1（ABCG1）的表达。此外，我们单独或共同用 LXR-623（LXR 激动剂）、胆固醇、衣霉素和盐霉素处理 HUVECs。结果表明，氧化应激诱导的 ED 可以使 LXRα 和 LXRβ 的表达失调，并引发 ER 应激和 Wnt/β-连环蛋白通路，从而导致胆固醇积累。此外，用胆固醇处理后也显示出类似的结果；然而，肝 X 受体（LXR）的激活可以逆转这些变化。此外，其他结果表明，衣霉素诱导的 ER 应激可以刺激胆固醇的积累和 Wnt/β-连环蛋白通路，进一步导致 ED。相反，盐霉素可以通过调节 Wnt/β-连环蛋白通路来逆转上述作用。总之，我们的结果表明，胆固醇外排部分负责氧化应激诱导的 ED；此外，ER 应激、Wnt/β-连环蛋白通路和胆固醇代谢可以相互作用，促进 ED。
