1,25(OH) 2 vitamin D inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus

Jisu Oh, Sherry Weng, Shaili K. Felton, Sweety Bhandare, Amy Riek, Boyd Butler, Brandon M. Proctor, Marvin Petty, Zhouji Chen, Kenneth B. Schechtman, Leon Bernal-Mizrachi, Carlos Bernal-Mizrachi

Research output: Contribution to journalArticle

257 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)687-698
Number of pages12
JournalCirculation
Volume120
Issue number8
DOIs
StatePublished - Aug 25 2009

Keywords

  • Atherosclerosis
  • Diabetes mellitus
  • Inflammation
  • Nutrition
  • Vitamin D

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