To investigate the effects of combination treatment with VDR and RXR agonists on preventing atherosclerosis associated with high-glucose injury in diabetic ApoE−/− mice and explored the underlying mechanisms in the levels of human vascular endothelial cells.Design and Method:
Diabetic ApoE−/− mice were treated with saline, VDR agonist calcitriol (10 μg/kg, twice a week), RXR agonist bexarotene (10 mg/kg, once daily), or calcitriol and bexarotene combined therapy for 12 weeks. Plaque areas of thoracic aorta were quantified by morphometric analysis. Local and circulatory levels of oxidative stress and inflammation indices were measured. The effects of naturally occurring VDR ligand 1α,25-dihydroxyvitamin D3 (1,25[OH]2D3), RXR ligand 9-cis retinoic acid (9-cis-RA), and their combination therapy on high-glucose-induced protein kinase C /NADPH oxidase/reactive oxygen species pathway activation were evaluated, Using human endothelial cells.Results:
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 indices of oxidative stress and inflammation to a greater extent than either monotherapy. In the in vitro study, 1,25[OH]2D3 and 9-cis-RA, both significantly inhibited high-glucose-induced endothelial cell apoptosis. Coadministration 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.Conclusions:
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.