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(Circulation. 2007;116:I-282 – I-287.)
© 2007 American Heart Association, Inc.

Surgery for Valvular Heart Disease

A Novel Role of the Sympatho-Adrenergic System in Regulating Valve Calcification

Lana Osman, BSc; Adrian H. Chester, PhD; Padmini Sarathchandra, PhD; Najma Latif, PhD; Wenfang Meng, MD, PhD; Patricia M. Taylor, PhD; Magdi H. Yacoub, FRS

From the Imperial College, NHLI, Heart Science Centre, Department of Cardiothoracic Surgery (L.O., A.H.C., P.S., N.L., P.M.T., M.H.Y.), Royal Brompton and Harefield NHS Trust, Harefield, Middlesex, UK; and S.R.R.S.H., Zhejiang University School of Medicine (W.M.), Hangzhou, P.R. China.

Correspondence to Professor Sir Magdi H. Yacoub, Imperial College London, Heart Science Centre, Harefield Hospital, Harefield, Middlesex. UB9 6JH, UK. E-mail m.yacoub{at}imperial.ac.uk

Background— Aortic valve calcification is a progressive process resembling ossification. Recent evidence indicates that the sympathetic nervous system plays an important role in regulating bone deposition and resorption through the ß ₂-adrenergic receptors (ß₂-ARs). The aim of this study is to determine the level and pattern of expression of ß₂-ARs in human valve interstitial cells (ICs) and assess their influence on differentiation of the cells into an osteoblast-like phenotype.

Methods and Results— Immunohistochemical analysis demonstrated a high expression of ß₂-ARs, ß₁-ARs, ß₃-AR,s and receptor activator of nuclear factor-B (RANK) in calcified aortic valves. The expression of ß₂-ARs and ß₁-ARs mRNA was assessed by real-time TaqMan PCR in cultures of human aortic valve ICs. Human valve ICs treated with the selective ß₂-AR agonist, salmeterol, in the presence of osteogenic medium showed a significant 5-fold decrease in the alkaline phosphatase (ALP) activity in comparison to cells treated with osteogenic medium only (P<0.05). Immunocytochemical staining of the valve ICs showed a concomitant reduction in osteocalcin expression. In addition, other ß₂-AR agonists caused a reduction in the protein expression of bone markers including ALP, Cbfa-1, and periostin. Human valve ICs treated with norepinephrine, in the presence of osteogenic medium, did not show a significant reduction in the ALP activity.

Conclusions— These findings suggest an important role of the ß₂-ARs in regulating valve calcification and may identify potential therapeutic targets.

Key Words: valves • calcification • ß adrenergic receptors • differentiation

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