Activation of nuclear factor-kappa B accelerates vascular calcification by inhibiting ankylosis protein homolog expression

Kidney Int. 2012 Jul;82(1):34-44. doi: 10.1038/ki.2012.40. Epub 2012 Mar 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / complications
  • Atherosclerosis / immunology
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Diphosphates / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Down-Regulation
  • Genes, Reporter
  • HEK293 Cells
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Inflammation Mediators / metabolism*
  • Kidney Failure, Chronic / complications
  • Kidney Failure, Chronic / immunology
  • Kidney Failure, Chronic / metabolism
  • Kidney Failure, Chronic / pathology
  • Male
  • Muscle, Smooth, Vascular / immunology
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / immunology
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Osteogenesis / genetics
  • Phosphate Transport Proteins / genetics
  • Phosphate Transport Proteins / metabolism*
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA Stability
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Time Factors
  • Transfection
  • Tristetraprolin / genetics
  • Tristetraprolin / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Calcification / etiology
  • Vascular Calcification / immunology
  • Vascular Calcification / metabolism*
  • Vascular Calcification / pathology

Substances

  • ANKH protein, human
  • Ankh protein, mouse
  • Diphosphates
  • I-kappa B Proteins
  • Inflammation Mediators
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Nfkbia protein, rat
  • Phosphate Transport Proteins
  • Tristetraprolin
  • Tumor Necrosis Factor-alpha
  • ZFP36 protein, human
  • NF-KappaB Inhibitor alpha
  • diphosphoric acid