Nuclear factor-κB-hypoxia-inducible factor-2 pathway in aortic valve stenosis

Hirokuni Akahori, Takeshi Tsujino, Yoshiro Naito, Hisashi Sawada, Masataka Sugahara, Miho Fukui, Mitsumasa Ohyanagi, Masataka Mitsuno, Yuji Miyamoto, Tohru Masuyama

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


BACKGROUND AND AIM OF THE STUDY: Valvular calcification is a prominent feature of aortic valve stenosis (AS), and calcified aortic valves share several features with bone tissue. Hypoxia-inducible factor-2 (HIF-2) is activated by nuclear factor-κB (NF-κB) and plays a critical role in an osteoblastic differentiation. The study aim was to determine whether the NF-κB-HIF-2 pathway is involved in the pathophysiology of calcified aortic valve disease.

METHODS: A total of 50 specimens of aortic valve leaflets obtained from patients who had undergone aortic valve replacement for AS was examined. The aortic valve leaflets from 10 patients with annulo-aortic ectasia (AAE) served as controls. The stenotic valve leaflets were examined using immunohistochemistry to detect NF-κB, HIF-2α, vascular endothelial growth factor (VEGF), vascular endothelial cells, and collagen X. The calcification area was measured and any correlation between the calcification area and NF-κB-HIF-2 pathway was assessed.

RESULTS: NF-κB and HIF-2α were expressed in the leaflets from patients with AS, but not in those from AAE controls. Both factors were expressed around massive calcified lesions, and HIF-2α was co-localized with NF-κB. VEGF, neoangiogenesis and collagen X were located in the area where HIF-2α was expressed, and correlated positively with HIF-2α expression. The calcification area correlated positively with collagen X expression.

CONCLUSION: The NF-κB-HIF-2 pathway was expressed in calcified aortic valves and associated with an increased expression of VEGF and collagen X. This signaling pathway may play important roles in the pathophysiology of AS.

Original languageEnglish
Pages (from-to)558-566
Number of pages9
JournalJournal of Heart Valve Disease
Issue number5
StatePublished - Sep 1 2014

ASJC Scopus subject areas

  • General Medicine


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