on August 10, 2009
Published online before print August 10, 2009, doi: 10.1161/CIRCULATIONAHA.109.856070
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Submitted on February 3, 2009
From Endocrinology, Metabolism, and Lipid Research, Department of Medicine (J.O., S.W., S.K.F., A.R., M.P., C.B.-M.), Division of Nephrology, Department of Pediatrics (S.B.), Department of Cell Biology and Physiology (B.B., C.B.-M.), Cardiovascular Division, Department of Medicine (B.M.P., K.B.S.), Geriatrics and Division of Nutritional Science, Department of Medicine (Z.C.), and Division of Biostatistics (K.B.S.), Washington University, St Louis, Mo, and Hematology/Oncology, Winship Cancer Institute, Emory University (L.B.-M.), Atlanta, Ga. * To whom correspondence should be addressed. E-mail: cbernal{at}dom.wustl.edu.
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 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 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)2D3 downregulation of c-Jun N-terminal kinase activation reduced peroxisome proliferated–activated receptor- 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.
Accepted on June 15, 2009
1,25(OH)2 Vitamin D Inhibits Foam Cell Formation and Suppresses Macrophage Cholesterol Uptake in Patients With Type 2 Diabetes Mellitus
Jisu Oh BS,
expression, suppressed CD36 expression, and prevented oxidized low-density lipoprotein–derived cholesterol uptake. In addition, 1,25(OH)2D3 suppression of macrophage endoplasmic reticulum stress improved insulin signaling, downregulated SR-A1 expression, and prevented oxidized and acetylated low-density lipoprotein–derived cholesterol uptake.
Key words: atherosclerosis • diabetes mellitus • inflammation • nutrition • vitamin D
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