1,25(OH)2 vitamin D suppresses macrophage migration and reverses atherogenic cholesterol metabolism in type 2 diabetic patients.
J Steroid Biochem Mol Biol
; 136: 309-12, 2013 Jul.
Article
em En
| MEDLINE
| ID: mdl-23333932
ABSTRACT
Reduced monocyte infiltration into the vessel wall and increased macrophage cholesterol efflux are critical components in atherosclerotic plaque regression. During inflammation, monocyte chemotactic protein 1 (MCP-1) signaling activation and cholesterol deposition in macrophages induce endoplasmic reticulum (ER) stress, which promotes an increased inflammatory response. Increased macrophage ER stress shifts macrophages into an M2 macrophage phenotype with increased cholesterol uptake and deposition. In type 2 diabetes, a population with elevated baseline risk of cardiovascular disease (CVD), vitamin D deficiency doubles that risk. We have found that 1,25-dihydroxy vitamin D [1,25(OH)2D] prevents foam cell formation during macrophage differentiation by suppressing ER stress. However, it is unknown whether suppression of ER stress by 1,25(OH)2D decreases monocyte infiltration and reverses atherogenic cholesterol metabolism in previously differentiated, vitamin D-deplete macrophages. We collected peripheral monocytes from type 2 diabetic patients and differentiated them into macrophages under vitamin D-deplete or 1,25(OH)2D-supplemented conditions. 1,25(OH)2D supplementation suppressed macrophage migration in response to MCP-1 and mRNA expression of chemokine (C-C motif) receptor 2 (CCR2), the MCP-1 receptor, compared to vitamin D-deplete cells. Furthermore, inhibition of ER stress with phenyl butyric acid resulted in similar effects even in vitamin D-deplete cells, while induction of ER stress with Thapsigargin under 1,25(OH)2D-supplemented conditions increased macrophage migration and CCR2 expression, suggesting that the effects of vitamin D on migration are mediated through ER stress suppression. To determine whether the detrimental pattern of macrophage cholesterol metabolism in vitamin D depletion is reversible, we assessed cholesterol uptake in macrophages differentiated under vitamin D-deplete conditions as described above, then supplemented with 1,25(OH)2D or maintained in vitamin D-deplete conditions. Cholesterol uptake was decreased in 1,25(OH)2D-supplemented compared to vitamin D-deplete cells, suggesting slowed cholesterol deposition with active vitamin D. 1,25(OH)2D supplementation also suppressed cholesteryl ester formation and enhanced cholesterol efflux in M2 macrophages compared to vitamin D-deplete cells, suggesting facilitation of cholesterol egress in the presence of 1,25(OH)2D. We thus provide further evidence that active vitamin D is an ER stress reliever that may have a role in atherosclerotic plaque regression. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vitamina D
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Inibição de Migração Celular
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Colesterol
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Diabetes Mellitus Tipo 2
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Macrófagos
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Anticolesterolemiantes
Limite:
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article