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(Circulation. 2006;114:I-566 – I-572.)
© 2006 American Heart Association, Inc.

Surgery for Valvular Heart Disease

A Novel Role of Extracellular Nucleotides in Valve Calcification

A Potential Target for Atorvastatin

Lana Osman, BSc; Adrian H. Chester, PhD; Mohamed Amrani, FRCS, PhD; Magdi H. Yacoub FRS; Ryszard T. Smolenski MD, PhD

From Imperial College (L.O., A.H.C., M.H.Y., R.T.S.), National Heart and Lung Institute, Heart Science Centre, Department of Cardiothoracic Surgery (M.A.), Royal Brompton and Harefield National Health Service Trust, Harefield, Middlesex, UK; and the Department of Biochemistry (R.T.S.), Medical University of Gdansk, Poland.

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

Background— Calcific aortic valve disease is a common condition and is associated with inflammatory changes and expression of osteoblast-like cell phenotypes, but the cellular mechanisms are unclear. Recent studies identified extracellular ATP and P2Y receptor cascade as important regulators of bone remodeling, whereas its breakdown product, adenosine, is known to have anti-inflammatory properties. We hypothesize that extracellular ATP and adenosine have important roles in regulating osteoblast differentiation in human valve interstitial cells, and that this can be a potential target for therapy.

Method and Results— Primary cultures of human valve interstitial cells (ICs) treated for 21 days with osteogenic media, ATP, and ATP--S (a stable agonist of the P2Y receptor) revealed a significant increase in alkaline phosphatase (ALP) (an osteoblast marker) activity and expression as measured using spectrophotometric assay and immunocytochemistry staining. Valve ICs treated with adenosine alone did not cause an increase in ALP activity; however, adenosine treatment decreased the ALP activity and expression induced by osteogenic media after 21 days of incubation. In addition, atorvastatin inhibited the activity of ALP induced by ATP in human valve ICs, and enzyme studies revealed that atorvastatin upregulated the breakdown of extracellular ATP into adenosine in human valve ICs after 24-hour treatment.

Conclusion— These findings identify a novel role for extracellular nucleotides in inducing osteoblast differentiation in human valve ICs in vitro and provide a potential therapeutic target for preventing the disease progression.

Key Words: adenosine • enzymes • statins • valves