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

Background-Cardiovascular disease is the leading cause of death among those with diabetes mellitus. Vitamin D deficiency is associated with an 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 mellitus, 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 4 control groups: obese, diabetic, hypertensive patients with normal vitamin D (group B; n = 15); obese, nondiabetic, hypertensive patients with vitamin D deficiency (group C; n = 25); and nonobese, nondiabetic, nonhypertensive patients with vitamin D deficiency (group D; n = 10) or sufficiency (group E; n = 10). Macrophages from the same patients in all groups were cultured in vitamin D-deficient or 1,25-dihydroxyvitamin D-3[1,25(OH)(2)D-3]-supplemented media and exposed to modified low-density lipoprotein cholesterol. 1,25(OH)(2)D-3 suppressed foam cell formation by reducing acetylated or oxidized low-density lipoprotein cholesterol uptake in diabetic subjects only. Conversely, deletion of the vitamin D receptor in macrophages from diabetic patients accelerated foam cell formation induced by modified LDL. 1,25(OH)(2)D-3 downregulation of c-Jun N-terminal kinase activation reduced peroxisome proliferated-activated receptor-gamma expression, suppressed CD36 expression, and prevented oxidized low-density lipoprotein-derived cholesterol uptake. In addition, 1,25(OH)(2)D-3 suppression of macrophage endoplasmic reticulum stress improved insulin signaling, downregulated SR-A1 expression, and prevented oxidized and acetylated low-density lipoprotein-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 diabetic subjects. (Circulation. 2009; 120: 687-698.)