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

Zhao G, Xu MJ, Zhao MM, Dai XY, Kong W, Wilson GM, Guan Y, Wang CY, Wang X - Kidney Int. (2012)

Bottom Line: Although chronic inflammation is one of the etiologic factors, the underlying mechanism is not fully understood.Furthermore, a rat chronic renal failure model, with increased serum TNF levels, activated NF-κB and decreased ANKH levels.Both human calcified atherosclerotic lesions and arteries from patients with chronic kidney disease had activated NF-κB and decreased ANKH expression.

View Article: PubMed Central - PubMed

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.

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.

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Calcium deposition, ANKH expression and phosphor-p65 level in the human aortic wall. (a~c) Atherosclerotic lesion samples were obtained from patients by directional atherectomy; (d~f) Aortic wall samples were obtained from patients with chronic kidney disease (CKD); (g~i) Aortic wall samples were obtained from healthy donors during renal transplantation. (a,d,g) von Kossa staining of calcium deposition. (b,e,h) Immunohistochemical staining of ANKH protein level. (c,f,i) Immunofluorescence staining (green) or immunohistochemical staining of p-p65 (s536) level. M= tunica media, A= adventitia.
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Figure 7: Calcium deposition, ANKH expression and phosphor-p65 level in the human aortic wall. (a~c) Atherosclerotic lesion samples were obtained from patients by directional atherectomy; (d~f) Aortic wall samples were obtained from patients with chronic kidney disease (CKD); (g~i) Aortic wall samples were obtained from healthy donors during renal transplantation. (a,d,g) von Kossa staining of calcium deposition. (b,e,h) Immunohistochemical staining of ANKH protein level. (c,f,i) Immunofluorescence staining (green) or immunohistochemical staining of p-p65 (s536) level. M= tunica media, A= adventitia.

Mentions: To further demonstrate that NF-κB negatively regulated ANKH expression in vivo, we investigated a possible inverse relation between NF-κB and ANKH expression in human artery walls of patients with CKD or atherosclerosis. Because the phosphorylation of p65 on Ser536 is associated with NF-κB activities, we used anti-phospho- NF-κB p65 (Ser536) antibodies to determine NF-κB activation. In human atherosclerotic lesions, ANKH protein was weakly detected in areas strongly stained with phosphorylated p65, where von kossa staining showed clear calcium deposition (Figure 7). Decreased ANKH protein level was also observed in calcified aortic walls from CKD patients with increased phosphorylation of p65 as compared with aortic walls from healthy donors. Therefore, NF-κB activation in local inflammation in the human aortic wall may augment calcification by downregulating ANKH.


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

Zhao G, Xu MJ, Zhao MM, Dai XY, Kong W, Wilson GM, Guan Y, Wang CY, Wang X - Kidney Int. (2012)

Calcium deposition, ANKH expression and phosphor-p65 level in the human aortic wall. (a~c) Atherosclerotic lesion samples were obtained from patients by directional atherectomy; (d~f) Aortic wall samples were obtained from patients with chronic kidney disease (CKD); (g~i) Aortic wall samples were obtained from healthy donors during renal transplantation. (a,d,g) von Kossa staining of calcium deposition. (b,e,h) Immunohistochemical staining of ANKH protein level. (c,f,i) Immunofluorescence staining (green) or immunohistochemical staining of p-p65 (s536) level. M= tunica media, A= adventitia.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376207&req=5

Figure 7: Calcium deposition, ANKH expression and phosphor-p65 level in the human aortic wall. (a~c) Atherosclerotic lesion samples were obtained from patients by directional atherectomy; (d~f) Aortic wall samples were obtained from patients with chronic kidney disease (CKD); (g~i) Aortic wall samples were obtained from healthy donors during renal transplantation. (a,d,g) von Kossa staining of calcium deposition. (b,e,h) Immunohistochemical staining of ANKH protein level. (c,f,i) Immunofluorescence staining (green) or immunohistochemical staining of p-p65 (s536) level. M= tunica media, A= adventitia.
Mentions: To further demonstrate that NF-κB negatively regulated ANKH expression in vivo, we investigated a possible inverse relation between NF-κB and ANKH expression in human artery walls of patients with CKD or atherosclerosis. Because the phosphorylation of p65 on Ser536 is associated with NF-κB activities, we used anti-phospho- NF-κB p65 (Ser536) antibodies to determine NF-κB activation. In human atherosclerotic lesions, ANKH protein was weakly detected in areas strongly stained with phosphorylated p65, where von kossa staining showed clear calcium deposition (Figure 7). Decreased ANKH protein level was also observed in calcified aortic walls from CKD patients with increased phosphorylation of p65 as compared with aortic walls from healthy donors. Therefore, NF-κB activation in local inflammation in the human aortic wall may augment calcification by downregulating ANKH.

Bottom Line: Although chronic inflammation is one of the etiologic factors, the underlying mechanism is not fully understood.Furthermore, a rat chronic renal failure model, with increased serum TNF levels, activated NF-κB and decreased ANKH levels.Both human calcified atherosclerotic lesions and arteries from patients with chronic kidney disease had activated NF-κB and decreased ANKH expression.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus