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lüll 1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus Oh J; Weng S; Felton SK; Bhandare S; Riek A; Butler B; Proctor BM; Petty M; Chen Z; Schechtman KB; Bernal-Mizrachi L; Bernal-Mizrachi CCirculation 2009[Aug]; 120 (8): 687-98BACKGROUND: 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. CONCLUSIONS: These results identify reduced vitamin D receptor signaling as a potential mechanism underlying increased foam cell formation and accelerated cardiovascular disease in diabetic subjects.|Adult[MESH]|Animals[MESH]|CD36 Antigens/genetics/metabolism[MESH]|Cells, Cultured[MESH]|Cholesterol/*metabolism[MESH]|Diabetes Mellitus, Type 2/*immunology/*metabolism[MESH]|Female[MESH]|Foam Cells/*drug effects/metabolism[MESH]|Humans[MESH]|JNK Mitogen-Activated Protein Kinases/metabolism[MESH]|Lipoproteins, LDL/metabolism[MESH]|Macrophages/cytology/*drug effects/metabolism[MESH]|Male[MESH]|Mice[MESH]|Mice, Mutant Strains[MESH]|Middle Aged[MESH]|Obesity/immunology/metabolism[MESH]|PPAR gamma/metabolism[MESH]|Receptors, Calcitriol/metabolism[MESH]|Scavenger Receptors, Class A/genetics/metabolism[MESH]|Signal Transduction/drug effects/immunology[MESH]|Vitamin D Deficiency/immunology/metabolism[MESH]|Vitamin D/*analogs & derivatives/pharmacology[MESH] |