Lin L M, Peng F, Liu Y P, Chai D J, Ning R B, Xu C S, Lin J X
The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China.
Department of Cardiology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
Atherosclerosis. 2016 Aug;251:273-281. doi: 10.1016/j.atherosclerosis.2016.06.005. Epub 2016 Jun 3.
Diabetes contributes to atherosclerosis partially through induction of oxidative stress. Both vitamin D receptor (VDR) and retinoid X receptor (RXR) agonists exhibit anti-atherogenic effects.
We explored the effects of combination treatment with VDR and RXR agonists (represented by calcitriol and bexarotene, respectively) on atherosclerosis progression and the mechanisms involved, using a diabetes model of mice. The animals were intragastrically fed calcitriol (200 ng/kg, twice-a-week), bexarotene (10 mg/kg, once-daily) either alone or in combination for 12 weeks.
VDR and RXR agonists delayed atherosclerosis progression independent of serum lipid and glucose levels, and significantly reduced the protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit gp91phox and nuclear factor-kappa B (NF-κB) subunit p65, as well as plasma biomarkers of oxidative stress and inflammation. Combination therapy alleviated atherosclerosis and inhibited indexes of oxidative stress and inflammation to a greater extent than either monotherapy. In the in vitro study, naturally occurring VDR ligand 1α,25-dihydroxyvitamin D3 (1,25[OH]2D3) and RXR ligand 9-cis retinoic acid (9-cis-RA), both significantly inhibited high-glucose-induced endothelial cell apoptosis. Co-administration of VDR and RXR ligands produced synergistic protection against endothelial apoptosis by antagonizing the protein kinase C /NADPH oxidase/reactive oxygen species pathway. The inhibitory effects of 9-cis-RA on oxidative stress was attenuated when VDR was downregulated by VDR siRNA; however, downregulation of RXR by RXR siRNA imposed no influence on the effects of 1,25(OH)2D3.
Combination treatment with VDR and RXR agonists synergistically alleviated diabetic atherosclerosis through inhibition of oxidative stress, and the preventive effects of RXR agonist may partially depend on VDR activation.
糖尿病部分通过诱导氧化应激促进动脉粥样硬化。维生素D受体（VDR）激动剂和维甲酸X受体（RXR）激动剂均具有抗动脉粥样硬化作用。
我们使用小鼠糖尿病模型，探讨VDR和RXR激动剂（分别以骨化三醇和贝沙罗汀为代表）联合治疗对动脉粥样硬化进展的影响及其相关机制。动物分别单独或联合灌胃给予骨化三醇（200 ng/kg，每周两次）、贝沙罗汀（10 mg/kg，每日一次），持续12周。
VDR和RXR激动剂延缓了动脉粥样硬化进展，且与血脂和血糖水平无关，并显著降低了烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶亚基gp91phox和核因子κB（NF-κB）亚基p65的蛋白表达，以及氧化应激和炎症的血浆生物标志物。联合治疗比单一治疗在更大程度上减轻了动脉粥样硬化，并抑制了氧化应激和炎症指标。在体外研究中，天然存在的VDR配体1α,25-二羟基维生素D3（1,25[OH]2D3）和RXR配体9-顺式维甲酸（9-顺式-RA）均显著抑制高糖诱导的内皮细胞凋亡。VDR和RXR配体共同给药通过拮抗蛋白激酶C/NADPH氧化酶/活性氧途径对内皮细胞凋亡产生协同保护作用。当VDR被VDR siRNA下调时，9-顺式-RA对氧化应激的抑制作用减弱；然而，RXR被RXR siRNA下调对1,25(OH)2D3的作用没有影响。
VDR和RXR激动剂联合治疗通过抑制氧化应激协同减轻糖尿病性动脉粥样硬化，RXR激动剂的预防作用可能部分依赖于VDR激活。
