Published online before print July 31, 2006, doi: 10.1161/CIRCULATIONAHA.105.591032
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(Circulation. 2006;114:565-573.)
© 2006 American Heart Association, Inc.
Heart Failure |
Inhibition of Urokinase-Type Plasminogen Activator or Matrix Metalloproteinases Prevents Cardiac Injury and Dysfunction During Viral Myocarditis
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.
Correspondence to Stephane Heymans, MD, PhD, Molecular and Experimental Cardiology, CARIM, Department of Cardiology, P. Debyelaan 25, PO Box 5800, 6202AZ Maastricht, The Netherlands. E-mail s.heymans{at}cardio.unimaas.nl
Received September 26, 2005; revision received February 24, 2006; accepted May 26, 2006.
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.
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