Vitamin D Protects Against Atherosclerosis via Regulation of Cholesterol Efflux and Macrophage Polarization in Hypercholesterolemic Swine
Objective—Prevalence of vitamin D (VD) deficiency and its association with the risk of cardiovascular disease prompted us to evaluate the effect of VD status on lipid metabolism and atherosclerosis in hypercholesterolemic microswine.
Approach and Results—Yucatan microswine were fed with VD-deficient (0 IU/d), VD-sufficient (1000 IU/d), or VD-supplemented (3000 IU/d) high-cholesterol diet for 48 weeks. Serum lipids and 25(OH)-cholecalciferol levels were measured biweekly. Histology and biochemical parameters of liver and arteries were analyzed. Effect of 1,25(OH)2D3 on cholesterol metabolism was examined in human HepG2 and THP-1 macrophage-derived foam cells. VD deficiency decreased plasma high-density lipoprotein levels, expression of liver X receptors, ATP-binding membrane cassette transporter A1, and ATP-binding membrane cassette transporter G1 and promoted cholesterol accumulation and atherosclerosis in hypercholesterolemic microswine. VD promoted nascent high-density lipoprotein formation in HepG2 cells via ATP-binding membrane cassette transporter A1–mediated cholesterol efflux. Cytochrome P450 (CYP)27B1 and VD receptor were predominantly present in the CD206+ M2 macrophage foam cell–accumulated cores in coronary artery plaques. 1,25(OH)2D3 increased the expression of liver X receptors, ATP-binding membrane cassette transporter A1, and ATP-binding membrane cassette transporter G1 and promoted cholesterol efflux in THP-1 macrophage–derived foam cells. 1,25(OH)2D3 decreased intracellular free cholesterol and polarized macrophages to M2 phenotype with decreased expression of tumor necrosis factor-α, interleukin-1β, interleukin-6 under LPS stimulation. 1,25(OH)2D3 markedly induced CYP27A1 expression via a VD receptor–dependent JNK1/2 signaling pathway and increased 27-hydroxycholesterol levels, which induced liver X receptors, ATP-binding membrane cassette transporter A1, and ATP-binding membrane cassette transporter G1 expression and stimulated cholesterol efflux that was inhibited by VD receptor antagonist and JNK1/2 signaling inhibitor in THP-1 macrophage–derived foam cell.
Conclusions—VD protects against atherosclerosis in hypercholesterolemic swine via controlling cholesterol efflux and macrophage polarization via increased CYP27A1 activation.
- cardivascular disease
- cholesterol efflux
- macrophage polarization
- vitamin D
- Received June 30, 2015.
- Accepted September 3, 2015.
- © 2015 The Authors.
Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.