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Arterioscler Thromb Vasc Biol. 2016 Aug;36(8):1651-9. doi: 10.1161/ATVBAHA.116.307586. Epub 2016 Jun 2.

Vitamin D Deficiency Accelerates Coronary Artery Disease Progression in Swine.

Author information

1
From the Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE.
2
From the Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE. dkagr@creighton.edu.

Abstract

OBJECTIVE:

The role of vitamin D deficiency in coronary artery disease (CAD) progression is uncertain. Chronic inflammation in epicardial adipose tissue (EAT) has been implicated in the pathogenesis of CAD. However, the molecular mechanism underlying vitamin D deficiency-enhanced inflammation in the EAT of diseased coronary arteries remains unknown. We examined a mechanistic link between 1,25-dihydroxyvitamin D-mediated suppression of nuclear factor-κB (NF-κB) transporter, karyopherin α4 (KPNA4) expression and NF-κB activation in preadipocytes. Furthermore, we determined whether vitamin D deficiency accelerates CAD progression by increasing KPNA4 and nuclear NF-κB levels in EAT.

APPROACH AND RESULTS:

Nuclear protein levels were detected by immunofluorescence and Western blot. Exogenous KPNA4 was transported into cells by a transfection approach and constituted lentiviral vector. Swine were administered vitamin D-deficient or vitamin D-sufficient hypercholesterolemic diet. After 1 year, the histopathology of coronary arteries and nuclear protein expression of EAT were assessed. 1,25-dihydroxyvitamin D inhibited NF-κB activation and reduced KPNA4 levels through increased vitamin D receptor expression. Exogenous KPNA4 rescued 1,25-dihydroxyvitamin D-dependent suppression of NF-κB nuclear translocation and activation. Vitamin D deficiency caused extensive CAD progression and advanced atherosclerotic plaques, which are linked to increased KPNA4 and nuclear NF-κB levels in the EAT.

CONCLUSIONS:

1,25-dihydroxyvitamin D attenuates NF-κB activation by targeting KPNA4. Vitamin D deficiency accelerates CAD progression at least, in part, through enhanced chronic inflammation of EAT by upregulation of KPNA4, which enhances NF-κB activation. These novel findings provide mechanistic evidence that vitamin D supplementation could be beneficial for the prevention and treatment of CAD.

KEYWORDS:

1,25-dihydroxyvitamin D; KPNA4; atherosclerosis; coronary artery disease; vitamin D

PMID:
27255724
PMCID:
PMC4965317
DOI:
10.1161/ATVBAHA.116.307586
[Indexed for MEDLINE]
Free PMC Article

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