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You are here: Contents > 2014 > Volume 23 Number 5 September 2014 > AORTIC VALVE DISEASE > Nuclear Factor-κB-Hypoxia-Inducible Factor-2 Pathway in Aortic Valve Stenosis

Nuclear Factor-κB-Hypoxia-Inducible Factor-2 Pathway in Aortic Valve Stenosis

Hirokuni Akahori1, Takeshi Tsujino2, Yoshiro Naito1, Hisashi Sawada1, Masataka Sugahara1, Miho Fukui1, Mitsumasa Ohyanagi3, Masataka Mitsuno4, Yuji Miyamoto4, Tohru Masuyama1

1Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, 2Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, 3Division of Coronary Heart Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, 4Department of Cardiovascular Surgery, Hyogo College of Medicine, Nishinomiya, Japan

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 annuloaortic 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.

The Journal of Heart Valve Disease 2014;23:558-566

Nuclear Factor-κB-Hypoxia-Inducible Factor-2 Pathway in Aortic Valve Stenosis

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