Inhibition of urokinase-type plasminogen activator or matrix metalloproteinases prevents cardiac injury and dysfunction during viral myocarditis

• Published in: Circulation (New York, N.Y.) Vol. 114; no. 6; pp. 565 - 573
• Main Authors: HEYMANS, Stephane, PAUSCHINGER, Matthias, PADALKO, Elisabeth, NEYTS, Johan, SCHULTHEISS, Heinz-Peter, VAN DE WERF, Frans, CARMELIET, Peter, PINTO, Yigal M, DE PALMA, Armando, KALLWELLIS-OPARA, Angela, RUTSCHOW, Susanne, SWINNEN, Melissa, VANHOUTTE, Davy, FANGYE GAO, TORPAI, Raimund, BAKER, Andrew H
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 08-08-2006
• Subjects: Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cytokines - analysis; Cytokines - genetics; Cytokines - physiology; Diabetes. Impaired glucose tolerance; Dilatation, Pathologic - pathology; Dilatation, Pathologic - physiopathology; Dilatation, Pathologic - prevention & control; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endomyocardial Fibrosis - pathology; Endomyocardial Fibrosis - physiopathology; Endomyocardial Fibrosis - prevention & control; Enterovirus B, Human; Enterovirus Infections - complications; Enterovirus Infections - physiopathology; Female; Fibrinolysin - analysis; Fibrinolysin - genetics; Fibrinolysin - physiology; Gene Expression Regulation - physiology; Heart; Heart - physiopathology; Heart - virology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Male; Management. Various non-drug treatments. Langerhans islet grafts; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases - analysis; Matrix Metalloproteinases - genetics; Matrix Metalloproteinases - physiology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocarditis - genetics; Myocarditis - physiopathology; Myocarditis - prevention & control; Myocarditis - virology; Myocardium - chemistry; Myocardium - pathology; Plasminogen Activator Inhibitor 1 - analysis; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - physiology; RNA, Messenger - analysis; RNA, Messenger - genetics; Tissue Inhibitor of Metalloproteinase-1 - analysis; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - physiology; Urokinase-Type Plasminogen Activator - analysis; Urokinase-Type Plasminogen Activator - antagonists & inhibitors; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - physiology; Myocarditis; Heart disease; Collagen; Glycoprotein; metalloproteinases; Cardiovascular disease; Plasminogen; plasminogen activators; Myocardial disease
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.105.591032

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.
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.
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.