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(Circulation Research. 2009;104:851.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Osteopontin

A Fibrosis-Related Marker Molecule in Cardiac Remodeling of Enterovirus Myocarditis in the Susceptible Host

Gudrun Szalay, Martina Sauter, Michael Haberland, Ulrich Zuegel, Andreas Steinmeyer, Reinhard Kandolf, Karin Klingel

From the Department of Molecular Pathology (G.S., M.S., M.H., R.K., K.K.), Institute for Pathology, University Hospital, Tübingen; and Common Mechanism Research Berlin (U.Z.) and Medicinal Chemistry Berlin (A.S.), Global Drug Discovery, BayerSchering Pharma AG, Berlin, Germany.

Correspondence to Prof Dr Karin Klingel, Department of Molecular Pathology, University Hospital Tübingen, Liebermeisterstr. 8, D-72076 Tübingen, Germany. E-mail karin.klingel{at}med.uni-tuebingen.de

The characteristics of dilated cardiomyopathy (DCM) resulting from chronic viral myocarditis are remodeling processes of the extracellular matrix. Based on our findings of enhanced osteopontin (OPN) expression in inflamed human hearts, we further investigated in the murine model of acute and chronic coxsackievirus (CV)B3-myocarditis the role of OPN regarding its involvement in resolution of cardiac virus infection and fibrosis. In hearts of A.BY/SnJ mice susceptible to chronic CVB3-myocarditis, a pronounced increase of OPN expression levels was detected by microarray analysis and quantitative RT-PCR during acute stages of myocarditis. Combined immunohistochemistry and in situ hybridization identified infiltrating macrophages as main OPN producers. In contrast to resistant C57BL/6 and OPN gene-deficient mice, transcription levels of matrix metalloproteinase-3, TIMP1 (tissue inhibitor of metalloproteinases-1), uPA (urokinase-type plasminogen activator), and transforming growth factor β1 were elevated in susceptible mice, and as a consequence, procollagen-1 mRNA expression and fibrosis was considerably enhanced. Treatment of infected susceptible mice with the vitamin D analog ZK 191784 led to decreased myocardial expression levels of OPN, metalloproteinase-3, TIMP1, uPA, and procollagen-1 and subsequently to reduced fibrosis. Concurrently, the fibrosis-relevant signaling molecules pERK (phosphorylated extracellular signal-regulated kinase) and pAkt (phosphorylated Akt), increased in A.BY/SnJ mice, were diminished in ZK 191784–treated mice. Here, we show that high expression levels of OPN in acute myocarditis are associated with consecutive development of extensive fibrosis that can be reduced by treatment with a vitamin D analog. Thus, OPN may serve as a diagnostic tool as well as a potential therapeutic target to limit cardiac remodeling in chronic myocarditis.

Key Words: myocarditis • infection • inflammation • remodeling • osteopontin

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