title: Vitamin D Deficiency Accelerates Coronary Artery Disease Progression in Swine.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: From the Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE.
authors.forename: Songcang
authors.initials: S
authors.lastname: Chen
authors.affiliation: From the Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE.
authors.forename: Vicki J
authors.initials: VJ
authors.lastname: Swier
authors.affiliation: From the Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE.
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Boosani
authors.affiliation: From the Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Radwan
authors.affiliation: From the Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE. dkagr@creighton.edu.
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Agrawal
mesh_terms: D021581:Active Transport, Cell Nucleus; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D006937:Hypercholesterolemia / Q000150:complications; D034622:RNA Interference; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology; D014808:Vitamin D Deficiency / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D028901:alpha Karyopherins / Q000235:genetics / Q000378:metabolism
chemical_list: C106259:KPNA4 protein, human; D018167:Receptors, Calcitriol; D051996:Transcription Factor RelA; D028901:alpha Karyopherins; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D
keywords: 1,25-dihydroxyvitamin D; KPNA4; atherosclerosis; coronary artery disease; vitamin D