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Although low levels of vitamin D have been known to double the risk of cardiovascular disease (CVD) in people with type 2 diabetes, an understanding of the underlying biological mechanisms have eluded scientists. Now, however, a research team at Washington University School of Medicine have investigated whether vitamin D deficiency contributes to an increase in macrophage-mediated cholesterol deposition in patients with diabetes, via a mechanism involving foam cell formation.
Macrophages were obtained from 76 obese, diabetic hypertensive patients with vitamin D deficiency (25-hydroxyvitamin D at below 80 nmol/litre). There were also 4 control groups from whom macrophages were also obtained: (1) obese hypertensive diabetics with normal vitamin D, (2) obese, non-diabetic, hypertensive patients with vitamin D deficiency, (3) non-obese, non-diabetic, non-hypertensive patients with vitamin D deficiency and (4) non-obese, non-diabetic, non-hypertensive patients with sufficient vitamin D. The macrophages from the same patients in all groups were cultured in vitamin D-deficient media, or in 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) supplemented media and then exposed to modified (acetylated or oxidised) LDL cholesterol.
For obese, hypertensive diabetics, macrophages cultured in the vitamin D deficient media showed a significant increase in foam cell formation induced by the oxidised or acetylated low density lipoproteins (LDL). Foam cells are derived from macrophages which have accumulated LDLs by a process of endocytosis, and are actively involved in forming atherosclerotic plaques in the endothelial lining of blood vessels. Macrophages from the same group of patients which had been treated with the active form of vitamin D (1,25(OH)2D3) and had been exposed to the modified LDL, had almost 50% less cholesteryl ester formation than the vitamin D deficient macrophages. Cholesteryl ester synthesis is also involved in the development of atherosclerosis. Additional tests on the cultured macrophages found that the deletion of the vitamin D receptor from the macrophages accelerated foam cell formation by modified LDL. Active vitamin D also influenced a number cellular signalling pathways (which are detailed in the article) which also prevented the deposition of cholesterol in the macrophages.
In diabetic patients with vitamin D deficiency, therefore, it is likely that macrophages loaded with cholesterol (i.e. foam cells) eventually build up, stiffen blood vessels and reduce blood flow, all of which are symptoms associated with cardiovascular disease. (Oh et al. Circulation. 2009;120 (8): 687-698; doi:10.1161/CIRCULATIONAHA.109.856070 ).
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