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

• Published in: Kidney international Vol. 82; no. 1; pp. 34 - 44
• Main Authors: Zhao, Gexin, Xu, Ming-Jiang, Zhao, Ming-Ming, Dai, Xiao-Yan, Kong, Wei, Wilson, Gerald M., Guan, Youfei, Wang, Cun-Yu, Wang, Xian
• Format: Journal Article
• Language: English
• Published: Basingstoke Elsevier Inc 01.07.2012; Nature Publishing Group; Elsevier Limited
• Subjects: Animal models; Animals; ANK protein; Aorta; Arteries; Arteriosclerosis; atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - complications; Atherosclerosis - immunology; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biological and medical sciences; Blood and lymphatic vessels; Calcification; Calcification (ectopic); Cardiology. Vascular system; Cardiovascular diseases; chronic kidney disease; Diabetes mellitus; Diphosphates - metabolism; Disease Models, Animal; Disease Progression; Down-Regulation; End-stage renal disease; Genes, Reporter; HEK293 Cells; Humans; I-kappa B Proteins - genetics; I-kappa B Proteins - metabolism; Inflammation; Inflammation Mediators - metabolism; inorganic phosphate; Kidney diseases; Kidney Failure, Chronic - complications; Kidney Failure, Chronic - immunology; Kidney Failure, Chronic - metabolism; Kidney Failure, Chronic - pathology; Kidneys; Male; Medical sciences; Membrane proteins; Mortality; Muscle, Smooth, Vascular - immunology; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - immunology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Nephrology. Urinary tract diseases; NF- Kappa B protein; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; nuclear factor-kappa B; Osteogenesis - genetics; Phosphate Transport Proteins - genetics; Phosphate Transport Proteins - metabolism; Promoter Regions, Genetic; pyrophosphates; Rats; Rats, Wistar; Renal failure; RNA Interference; RNA Stability; Secretion; Signal Transduction; Time Factors; Transfection; Tristetraprolin - genetics; Tristetraprolin - metabolism; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism; Urinary system involvement in other diseases. Miscellaneous; Vascular Calcification - etiology; Vascular Calcification - immunology; Vascular Calcification - metabolism; Vascular Calcification - pathology; atherosclerosis; nuclear factor-kappa B; chronic kidney disease; inorganic phosphate; tumor necrosis factor; Kidney disease; Phosphates; Nephrology; Urinary system disease; Ankylosis; Cytokine; Cardiovascular disease; Activation; Chronic kidney disease; Protein; Urology; Vascular disease; Tumor necrosis factor; Blood vessel; Renal failure; Atherosclerosis; Calcification; Circulatory system; Transcription factor NFκB
• ISSN: 0085-2538; 1523-1755; 1523-1755
• DOI: 10.1038/ki.2012.40

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.