TY - JOUR
T1 - 1,25(OH) 2 vitamin D inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus
AU - Oh, Jisu
AU - Weng, Sherry
AU - Felton, Shaili K.
AU - Bhandare, Sweety
AU - Riek, Amy
AU - Butler, Boyd
AU - Proctor, Brandon M.
AU - Petty, Marvin
AU - Chen, Zhouji
AU - Schechtman, Kenneth B.
AU - Bernal-Mizrachi, Leon
AU - Bernal-Mizrachi, Carlos
PY - 2009/8/25
Y1 - 2009/8/25
N2 - 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) 2D 3] -supplemented media and exposed to modified low-density lipoprotein cholesterol. 1,25(OH) 2D 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) 2D 3 downregulation of c-Jun N-terminal kinase activation reduced peroxisome proliferated-activated receptor-γ expression, suppressed CD36 expression, and prevented oxidized low-density lipoprotein-derived cholesterol uptake. In addition, 1,25(OH) 2D 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.
AB - 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) 2D 3] -supplemented media and exposed to modified low-density lipoprotein cholesterol. 1,25(OH) 2D 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) 2D 3 downregulation of c-Jun N-terminal kinase activation reduced peroxisome proliferated-activated receptor-γ expression, suppressed CD36 expression, and prevented oxidized low-density lipoprotein-derived cholesterol uptake. In addition, 1,25(OH) 2D 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.
KW - Atherosclerosis
KW - Diabetes mellitus
KW - Inflammation
KW - Nutrition
KW - Vitamin D
UR - http://www.scopus.com/inward/record.url?scp=69549116323&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.109.856070
DO - 10.1161/CIRCULATIONAHA.109.856070
M3 - Article
C2 - 19667238
AN - SCOPUS:69549116323
SN - 0009-7322
VL - 120
SP - 687
EP - 698
JO - Circulation
JF - Circulation
IS - 8
ER -