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(Circulation. 2009;120:687-698.)
© 2009 American Heart Association, Inc.

Vascular Medicine

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^*; Sherry Weng, MD^*; Shaili K. Felton, MD; Sweety Bhandare, MD; Amy Riek, MD; Boyd Butler, PhD; Brandon M. Proctor, PhD; Marvin Petty, BS; Zhouji Chen, MD, PhD; Kenneth B. Schechtman, PhD; Leon Bernal-Mizrachi, MD; Carlos Bernal-Mizrachi, MD

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.

Correspondence to Carlos Bernal-Mizrachi, Washington University School of Medicine, Campus Box 8127, 660 S Euclid Ave, St. Louis, MO 63110. E-mail cbernal{at}dom.wustl.edu

Received February 3, 2009; accepted June 15, 2009.

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- 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.

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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 120: 647-648. [Extract] [Full Text]