Department of Pharmacology, Nantong University Pharmacy College, Nantong 226001, China.
Department of Pharmacology, Nantong University Pharmacy College, Nantong 226001, China.
Biochem Pharmacol. 2021 Jun;188:114559. doi: 10.1016/j.bcp.2021.114559. Epub 2021 Apr 17.
Retinoid X receptor beta (RXRβ) has been poorly studied in atherosclerosis. The aim of the present study is to explore the function of RXRβ in oxidized low density lipoprotein (ox-LDL)-induced inflammation in endothelial cells and the underlying mechanism. The protein expression of RXRβ in the aorta of atherosclerotic mice was detected. A lentivirus vector for RXRβ overexpression and RNA interference for RXRβ downregulation were constructed and transfected into human aortic endothelial cells (HAECs). The results showed that RXRβ protein expression was downregulated in aorta of high fat diet (HFD)-fed LDLr mice and ox-LDL-treated HAECs. The ox-LDL-induced production of pro-inflammatory cytokines and activations of TLR9/NF-κB and NLRP3/caspase-1 inflammasome pathway were significantly decreased by RXRβ overexpression but increased by RXRβ knockdown in HAECs. The ox‑LDL‑induced mitochondrial damage indicated as the increased generation of mitochondrial ROS, decreased mitochondrial membrane potential and increased mitochondrial DNA release was abolished by RXRβ overexpression but aggravated by RXRβ knockdown. Treatment with mito-TEMPO significantly reduced the increased production of pro-inflammatory cytokines and activations of TLR9/NF-κB and NLRP3/caspase-1 inflammasome induced by RXRβ knockdown in ox-LDL treated HAECs. Moreover, peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α) protein expression was reduced in HFD-fed LDLr mice. RXRβ could interact with PGC1α in HAECs. Ox-LDL-induced reduction of PGC1α was significantly inhibited by RXRβ overexpression and aggravated by RXRβ downregulation. Our further study showed that transfection of PGC1α siRNA abrogated the alleviative effects of RXRβ overexpression on mitochondrial damage and inflammation in ox-LDL treated cells. The present study indicates that RXRβ exerted protective effects against the ox-LDL-induced inflammation may through regulating PGC1α-dependent mitochondrial homeostasis.
视黄醇 X 受体β（RXRβ）在动脉粥样硬化中的研究甚少。本研究旨在探讨 RXRβ在氧化型低密度脂蛋白（ox-LDL）诱导的内皮细胞炎症中的作用及其机制。检测了动脉粥样硬化小鼠主动脉中 RXRβ 的蛋白表达。构建了 RXRβ 过表达的慢病毒载体和 RXRβ 下调的 RNA 干扰，并转染到人主动脉内皮细胞（HAEC）中。结果显示，高脂饮食（HFD）喂养的 LDLr 小鼠和 ox-LDL 处理的 HAEC 中主动脉 RXRβ 蛋白表达下调。RXRβ 过表达可显著降低 ox-LDL 诱导的促炎细胞因子产生和 TLR9/NF-κB 和 NLRP3/caspase-1 炎性小体途径的激活，而 RXRβ 下调则增加了 HAEC 中的这些作用。RXRβ 过表达可消除 ox-LDL 诱导的线粒体损伤，表现为线粒体 ROS 生成增加、线粒体膜电位降低和线粒体 DNA 释放增加，而 RXRβ 下调则加剧了这种损伤。mito-TEMPO 处理可显著降低 ox-LDL 处理的 HAEC 中 RXRβ 下调诱导的促炎细胞因子产生和 TLR9/NF-κB 和 NLRP3/caspase-1 炎性小体途径的激活。此外，HFD 喂养的 LDLr 小鼠中过氧化物酶体增殖物激活受体-γ 共激活因子 1α（PGC1α）蛋白表达降低。RXRβ 可与 HAEC 中的 PGC1α 相互作用。RXRβ 过表达可显著抑制 ox-LDL 诱导的 PGC1α 减少，而 RXRβ 下调则加剧了这种减少。我们的进一步研究表明，转染 PGC1α siRNA 可消除 RXRβ 过表达对 ox-LDL 处理细胞线粒体损伤和炎症的缓解作用。本研究表明，RXRβ 通过调节 PGC1α 依赖性线粒体稳态发挥对 ox-LDL 诱导的炎症的保护作用。
