Vitamin D Suppression of Endoplasmic Reticulum Stress Promotes an Antiatherogenic Monocyte/Macrophage Phenotype in Type 2 Diabetic Patients

• Type of Material: Article
• Authors: Amy E. Riek, Washington University in St. Louis; Jisu Oh, Washington University in St. Louis; Jennifer E. Sprague, Washington University in St. Louis; Alexandra Timpson, Washington University in St. Louis; Lisa de las Fuentes, Washington University in St. Louis; Leon Bernal-Mizrachi, Emory University; Kenneth B. Schechtman, Washington University in St. Louis; Carlos Bernal-Mizrachi, Washington University in St. Louis
• Language: English
• Date: 2012-11-09
• Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
• Publication Version: Final Published Version
• Copyright Statement: © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M112.386912
• Title of Journal or Parent Work: JOURNAL OF BIOLOGICAL CHEMISTRY
• Volume: 287
• Issue: 46
• Start Page: 38482
• End Page: 38494
• Grant/Funding Information: Supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award 2 T32 HD043010 from the NICHD.; Supported by the Endocrine Society, the Endocrine Fellows Foundation, National Institutes of Health UL1RR024992/Sub-Award KL2RR024994 from the National Institutes of Health National Center for Research Resources, National Institutes of Health UL1TR000448/Sub-Award KL2TR000450 from the National Center for Advancing Translational Sciences, and the National Institutes of Health Roadmap for Medical Research.; This work was supported, in whole or in part, by National Institutes of Health Grants R01HL094818-0 and P30DK079333. This work was also supported by American Diabetes Association Grant 1-12-CT-08.
• Keywords: PROINFLAMMATORY CYTOKINE; CD14+CD16+ MONOCYTES; Biochemistry & Molecular Biology; ALTERNATIVE ACTIVATION; UNFOLDED PROTEIN RESPONSE; MACROPHAGE DIFFERENTIATION; Life Sciences & Biomedicine; Science & Technology; SUBCLINICAL ATHEROSCLEROSIS; ADHESION MOLECULES; INSULIN-RESISTANCE; MONOCYTE-DERIVED CELLS; ADVANCED ATHEROSCLEROTIC LESIONS
• Research Categories: Biology, Cell

Abstract

Cardiovascular disease is the leading cause of morbidity/mortality in patients with type 2 diabetes mellitus (T2DM), but there is a lack of knowledge about the mechanism(s) of increased atherosclerosis in these patients. In patients with T2DM, the prevalence of 25-hydroxy vitamin D (25(OH)D) deficiency is almost twice that for nondiabetics and doubles the relative risk of developing cardiovascular disease compared with diabetic patients with normal 25(OH)D. We tested the hypothesis that monocytes from vitamin D-deficient subjects will have a proatherogenic phenotype compared with vitamin D-sufficient subjects in 43 patients with T2DM. Serum 25(OH)D level inversely correlated with monocyte adhesion to endothelial cells even after adjustment for demographic and comorbidity characteristics. Vitamin D-sufficient patients (≥30 ng/ml 25(OH)D) had lower monocyte endoplasmic reticulum (ER) stress, a predominance of M1 over M2 macrophage membrane receptors, and decreased mRNA expression of monocyte adhesion molecules PSGL-1, β1-integrin, and β2-integrin compared with patients with 25(OH)D levels of <30 ng/ml. In vitamin D-deficient macrophages, activation of ER stress increased adhesion and adhesion molecule expression and induced an M2-predominant phenotype. Moreover, adding 1,25(OH)2D3 to vitamin D-deficient macrophages shifted their phenotype toward an M1-predominant phenotype with suppressed adhesion. Conversely, deletion of the vitaminDreceptor in macrophages from diabetic patients activated ER stress, accelerated adhesion, and increased adhesion molecule expression. The absence of ER stress protein CCAAT enhancer-binding protein homologous protein suppressed monocyte adhesion, adhesion molecule expression, and the M2-predominant phenotype induced by vitamin D deficiency. Thus, vitamin D is a natural ER stress reliever that induced an antiatherogenic monocyte/macrophage phenotype.