1,25(OH) ₂ Vitamin D Inhibits Foam Cell Formation and Suppresses Macrophage Cholesterol Uptake in Patients With Type 2 Diabetes Mellitus

Abstract

Background Cardiovascular disease is the leading cause of death among diabetics. Vitamin D deficiency is associated with increased risk of cardiovascular disease in this population. To determine the mechanism by which vitamin D deficiency mediates accelerated cardiovascular disease in patients with diabetes, we investigated the effects of active vitamin D on macrophage cholesterol deposition. Methods and Results We obtained macrophages from 76 obese, diabetic, hypertensive patients with vitamin D deficiency (25-hydroxyvitamin D < 80 nmol/L)(group A) and four control groups: obese, diabetic, hypertensive patients with normal vitamin D (group B, n=15), obese, non-diabetic, hypertensive patients with vitamin D deficiency (group C, n=25), and non-obese, non-diabetic, non-hypertensive patients with vitamin D deficiency (group D, n=10) or sufficiency (group E, n=10). The same patient’s macrophages from all groups were cultured in vitamin D-deficient or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) supplemented media and exposed to modified low-density lipoprotein cholesterol. 1,25(OH)2D3 suppressed foam cell formation by reducing acetylated or oxidized low-density lipoprotein cholesterol uptake in diabetics only. Conversely, deletion of the vitamin D receptor in macrophages from diabetic patients accelerated foam-cell formation induced by modified LDL. 1,25(OH)2D3 downregulation of c-Jun N-terminal kinase activation reduced PPARγ expression, suppressed CD36 expression, and prevented oxLDL-derived cholesterol uptake. In addition, 1,25(OH)2D3 suppression of macrophage endoplasmic reticulum stress improved insulin signaling, downregulated SR-A1expression, and prevented oxLDL and AcLDL-derived cholesterol uptake. Conclusion These results identify reduced vitamin D receptor signaling as a potential mechanism underlying increased foam-cell formation and accelerated cardiovascular disease in diabetics.

Vitamin D Suppression of Endoplasmic Reticulum Stress Promotes an Antiatherogenic Monocyte/Macrophage Phenotype in Type 2 Diabetic Patients

“…In circulating monocytes from vitamin D-deficient subjects, we observed activation of ER stress, increased adhesion and adhesion molecule expression, and an M2-predominant phenotype. In this study and our previous studies of macrophages from diabetic patients, VDR signaling activation suppressed ER stress, decreased macrophage foam cell formation by suppressing scavenger receptor CD36 and SR-AI expression, and promoted differentiation into the M1 phenotype (15,41). Interestingly, other studies indicate that M1 macrophages dominate advanced plaques and are considered to be proinflammatory, whereas M2 macrophages predominate in early plaques, rapidly accumulate small lipid droplets, and are anti-inflammatory, suggesting that vitamin D may induce proinflammatory effects despite suppression of macrophage cholesterol deposition (6,14,(53)(54)(55)(56).…”

“…During monocyte differentiation, the ER reorganizes both structurally and functionally to carry out new cell functions, leading to ER stress (39,40). We have shown that 1,25(OH) 2 D 3 suppresses ER stress in macrophages from diabetic patients and prevents foam cell formation, indicating that active vitamin D modulates macrophage atherogenic properties through an ER stress-dependent mechanism (41). Furthermore, we have shown that the suppression of ER stress shifts M2-predominant macrophages to M1-predominant cells and decreases foam cell formation, suggesting that regulation of ER stress by vitamin D could be a potential therapy for atherosclerosis.…”

“…3, C and D decrease in CD163 and MR, a significant increase in the MPR to Ͼ1, and decreased adhesion to fibronectin when compared with macrophages maintained in vitamin D-deficient conditions (Fig. 3, F (41). Thus, we first evaluated whether ex vivo monocytes from vitamin D-deficient nondiabetic controls and diabetics have increased ER stress.…”

The effect of different doses of vitamin D3 on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial

“…Although small study numbers limited the statistical power of our study to demonstrate a difference in FMD, it is less clear why the magnitude of the effect was smaller than that observed in our previous study; participants had similarly impaired endothelial function in both studies, and had similar blood pressure and baseline 25OHD levels. Although the mechanisms by which vitamin D may affect vascular health are not well elucidated [21], more patients in the current study were taking statins and ACE inhibitors at baseline; vitamin D can block renin production in animal models [22] and has been postulated to have actions similar to statins [23], perhaps by inhibiting uptake of cholesterol by macrophages and reducing foam cell formation [24]. Thus the mechanisms by which vitamin D improves endothelial function may have already been actuated by other medications; indeed cholesterol levels were well controlled and neither renin or aldosterone levels changed significantly with vitamin D supplementation in the current study.…”

The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications

“…73 Oh et al 74 reported that vitamin D-deficient obese individuals (primarily African-American) with hypertension and type-2 diabetes showed reduced foam cell formation when their macrophages were incubated with 1,25-dihydroxyvitamin D 3 and oxidized low-density lipoprotein (compared with macrophages incubated in vitamin D-deficient media); the effect appeared to be mediated by the vitamin D receptor. Under similar conditions, macrophages from obese control subjects with hypertension, but not type-2 diabetes, failed to show this reduction, suggesting that there may be a synergistic effect of diabetes and vitamin D deficiency on the propensity toward foam cell formation.…”