title: Activation of nuclear factor-kappa B accelerates vascular calcification by inhibiting ankylosis protein homolog expression.
abstract: Vascular calcification is a major risk factor of cardiovascular mortality, particularly for patients with end-stage renal disease and diabetes. Although chronic inflammation is one of the etiologic factors, the underlying mechanism is not fully understood. To clarify this, we studied how nuclear factor-kappa B (NF-κB) induction, a mediator of inflammation, might promote vascular calcification. Activation of NF-κB by tumor necrosis factor (TNF) promoted inorganic phosphate-induced calcification in human aortic smooth muscle cells. Pyrophosphate (an inhibitor of calcification) efflux to the extracellular matrix was suppressed along with the decreased expression of ankylosis protein homolog (ANKH), a transmembrane protein that controls pyrophosphate efflux of cells. The restoration of ANKH expression in these cells overcame the decreased pyrophosphate efflux and calcification. Tristetraprolin, a downstream product of NF-κB activation, may mediate destabilization of ANKH mRNA as its knockdown by shRNA increased ANKH expression and decreased calcification. Furthermore, a rat chronic renal failure model, with increased serum TNF levels, activated NF-κB and decreased ANKH levels. In contrast, the inhibition of NF-κB maintained ANKH expression and attenuated vascular calcification both in vivo and in vitro. Both human calcified atherosclerotic lesions and arteries from patients with chronic kidney disease had activated NF-κB and decreased ANKH expression. Thus, TNF-activated NF-κB promotes inflammation-accelerated vascular calcification by inhibiting ankylosis protein homolog expression and consequent pyrophosphate secretion.
authors.affiliation: Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Science, School of Basic Medical Science, Peking University Health Science Center, Ministry of Education, Beijing, PR China.
authors.forename: Gexin
authors.initials: G
authors.lastname: Zhao
authors.forename: Ming-Jiang
authors.initials: MJ
authors.lastname: Xu
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhao
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Dai
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Wilson
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.forename: Cun-Yu
authors.initials: CY
authors.lastname: Wang
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011756:Diphosphates / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D028061:Phosphate Transport Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D020871:RNA Stability; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D061205:Vascular Calcification / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: C498770:ANKH protein, human; C498769:Ankh protein, mouse; D011756:Diphosphates; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D028061:Phosphate Transport Proteins; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497552:ZFP36 protein, human; D000072000:NF-KappaB Inhibitor alpha; C107241:diphosphoric acid