Published Online
on July 31, 2006

A more recent version of this article appeared on August 8, 2006

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Submitted on September 26, 2005
Revised on February 24, 2006
Accepted on May 26, 2006

Inhibition of Urokinase-Type Plasminogen Activator or Matrix Metalloproteinases Prevents Cardiac Injury and Dysfunction During Viral Myocarditis

Stephane Heymans MD, PhD^*, Matthias Pauschinger MD, PhD, Armando De Palma MD, Angela Kallwellis-Opara PhD, Susanne Rutschow MS, Melissa Swinnen MS, Davy Vanhoutte MS, Fangye Gao PhD, Raimund Torpai MD, Andrew H. Baker PhD, Elisabeth Padalko MD, PhD, Johan Neyts MD, PhD, Heinz-Peter Schultheiss MD, PhD, Frans Van de Werf MD, PhD, Peter Carmeliet MD, PhD, and Yigal M. Pinto MD, PhD

From Experimental and Molecular Cardiology (S.H., M.S., Y.M.P.), CARIM, Maastricht University, Maastricht, the Netherlands; Center of Transgene Technology and Gene Therapy, VIB (S.H., D.V., F.G., P.C.), Department of Cardiology (F.V.d.W.), and Rega Institute Laboratory of Virology (A.D.P., E.P., J.N.), University of Leuven, Leuven, Belgium; Department of Cardiology, Charité University Hospital (M.P., A.K.-O., S.R., R.T., H.-P.S.), Berlin, Germany; and BHF Blood Pressure Group (A.H.B.), Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland.

^* To whom correspondence should be addressed. E-mail: s.heymans{at}cardio.unimaas.nl.

Background--Acute viral myocarditis is an important cause of cardiac failure in young adults for which there is no effective treatment apart from general heart failure therapy. The present study tested the hypothesis that increased expression of the proteinases urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) is implicated in cardiac inflammation, injury, and subsequent failure during Coxsackievirus-B3 (CVB3)-induced myocarditis.

Methods and Results--First, we showed increased expression and activity of uPA and MMP-9 in wild-type mice at 7 days of CVB3-induced myocarditis. Targeted deletion of uPA, which resulted in reduced MMP activity and cytokine expression or inhibition of MMPs by adenoviral gene overexpression of tissue inhibitor of metalloproteinases-1, decreased cardiac inflammation and reduced myocardial necrosis at 7 days and decreased cardiac fibrosis at 35 days after CVB3 infection. Importantly, loss of uPA or MMP activity prevented CVB3-induced cardiac dilatation and dysfunction, as determined by serial echocardiography.

Conclusions--Loss of uPA or MMP activity reduces the cardiac inflammatory response after CVB3 infection, thereby protecting against cardiac injury, dilatation, and failure during CVB3-induced myocarditis.

Key words: myocarditis • metalloproteinases • plasminogen activators • collagen

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