This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 120/8/687    most recent CIRCULATIONAHA.109.856070v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Oh, J. Articles by Bernal-Mizrachi, C. PubMed PubMed Citation Articles by Oh, J. Articles by Bernal-Mizrachi, C. Related Collections Lipids Pathophysiology Risk Factors Cell signalling/signal transduction Gene expression Gene regulation Type 2 diabetes Mechanism of atherosclerosis/growth factors Related Article

(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.

---

 

CLINICAL PERSPECTIVE

Related Article:

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

This article has been cited by other articles:

				I. Tabas, A. Tall, and D. Accili The Impact of Macrophage Insulin Resistance on Advanced Atherosclerotic Plaque Progression Circ. Res., January 8, 2010; 106(1): 58 - 67. [Abstract] [Full Text] [PDF]