PMID- 23012375
OWN - NLM
STAT- MEDLINE
DCOM- 20130131
LR  - 20220409
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 46
DP  - 2012 Nov 9
TI  - Vitamin D suppression of endoplasmic reticulum stress promotes an antiatherogenic 
      monocyte/macrophage phenotype in type 2 diabetic patients.
PG  - 38482-94
LID - 10.1074/jbc.M112.386912 [doi]
AB  - 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, beta(1)-integrin, and beta(2)-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)(2)D(3) to vitamin 
      D-deficient macrophages shifted their phenotype toward an M1-predominant 
      phenotype with suppressed adhesion. Conversely, deletion of the vitamin D 
      receptor 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.
FAU - Riek, Amy E
AU  - Riek AE
AD  - Division of Endocrinology, Metabolism, and Lipid Research, Washington University, 
      St. Louis, Missouri 63110, USA.
FAU - Oh, Jisu
AU  - Oh J
FAU - Sprague, Jennifer E
AU  - Sprague JE
FAU - Timpson, Alexandra
AU  - Timpson A
FAU - de las Fuentes, Lisa
AU  - de las Fuentes L
FAU - Bernal-Mizrachi, Leon
AU  - Bernal-Mizrachi L
FAU - Schechtman, Kenneth B
AU  - Schechtman KB
FAU - Bernal-Mizrachi, Carlos
AU  - Bernal-Mizrachi C
LA  - eng
GR  - R01HL094818-0/HL/NHLBI NIH HHS/United States
GR  - P30DK079333/DK/NIDDK NIH HHS/United States
GR  - UL1TR000448/KL2TR000450/TR/NCATS NIH HHS/United States
GR  - UL1RR024992/KL2RR024994/RR/NCRR NIH HHS/United States
GR  - R01 HL094818/HL/NHLBI NIH HHS/United States
GR  - UL1 TR000448/TR/NCATS NIH HHS/United States
GR  - P30 DK079333/DK/NIDDK NIH HHS/United States
GR  - 2 T32 HD043010/HD/NICHD NIH HHS/United States
GR  - KL2 TR000450/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120924
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (CD18 Antigens)
RN  - 0 (Integrin beta1)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (P-selectin ligand protein)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 1406-16-2 (Vitamin D)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Atherosclerosis/*pathology
MH  - CD18 Antigens/biosynthesis
MH  - Cell Adhesion
MH  - Cell Differentiation
MH  - Cross-Sectional Studies
MH  - Diabetes Mellitus, Type 2/*metabolism
MH  - Endoplasmic Reticulum/*metabolism
MH  - Female
MH  - Humans
MH  - Integrin beta1/biosynthesis
MH  - Macrophages/*cytology
MH  - Male
MH  - Membrane Glycoproteins/biosynthesis
MH  - Middle Aged
MH  - Monocytes/*cytology
MH  - Phenotype
MH  - RNA, Messenger/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Vitamin D/*metabolism
PMC - PMC3493893
EDAT- 2012/09/27 06:00
MHDA- 2013/02/01 06:00
PMCR- 2013/11/09
CRDT- 2012/09/27 06:00
PHST- 2012/09/27 06:00 [entrez]
PHST- 2012/09/27 06:00 [pubmed]
PHST- 2013/02/01 06:00 [medline]
PHST- 2013/11/09 00:00 [pmc-release]
AID - S0021-9258(20)62314-6 [pii]
AID - M112.386912 [pii]
AID - 10.1074/jbc.M112.386912 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 Nov 9;287(46):38482-94. doi: 10.1074/jbc.M112.386912. Epub 2012 
      Sep 24.