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(Circulation. 2008;117:1574-1582.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Ablation of Matrix Metalloproteinase-9 Increases Severity of Viral Myocarditis in Mice

Caroline Cheung, PhD^*; David Marchant, PhD^*; Elizabeth K.-Y. Walker, BSc; Zongshu Luo, MSc; Jingchun Zhang, MD; Bobby Yanagawa, PhD; Maziar Rahmani, MD, PhD; Jennifer Cox, BSc; Christopher Overall, MDS, PhD; Robert M. Senior, MD; Honglin Luo, MD; Bruce M. McManus, MD, PhD

From the Department of Pathology and Laboratory Medicine (C.C., D.M., E.K.-Y.W., Z.L., J.Z., B.Y., M.R., H.L., B.M.M.), The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul’s Hospital/Providence Health Care, and the Department of Oral Biological & Medical Sciences (J.C., C.O.), Centre for Blood Research, Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada; and the Division of Pulmonary and Critical Care Medicine (R.M.S.), Department of Medicine, Washington University School of Medicine and Barnes-Jewish Hospital, St Louis, Mo.

Correspondence to Dr Bruce McManus, The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul’s Hospital/Providence Health Care Research Institute, Room 166 1081 Burrard St, British Columbia, Canada V6Z 1Y6. E-mail bmcmanus{at}mrl.ubc.ca

Received April 30, 2007; accepted January 11, 2008.

Background— Coxsackievirus B3 (CVB3) causes human myocarditis, which can result in cardiac damage, maladaptive remodeling, and heart failure. Matrix metalloproteinases (MMP)-8 and -9 have been identified in virus-infected myocardium, but their particular roles and underlying mechanisms of effect are unknown. For the first time, we examine the severity of CVB3-induced myocarditis in MMP-8–and MMP-9–deficient mice.

Methods and Results— CVB3-infected MMP-8 and MMP-9 knockout (KO) mice and corresponding wild-type (WT) mice were euthanized and harvested at 9 days after infection. Expression of MMP-2, -8, -12, and -13 and tissue inhibitors of MMPs was assessed by zymography or immunoblotting on harvested hearts, and in situ hybridization was performed to detect active infection. Infected MMP-9 KO mice had greater myocardial injury and foci of infection than WT mice despite similar pancreatic infection. Increased fibrosis (10.6±2.7% versus 7.1±2.6%, P=0.04), viral titer, as well as decreased cardiac output, were evident in MMP-9 KO compared with WT mice as assessed by picrosirius red staining, plaque assay, and echocardiography, respectively. Immune infiltration was also greatly increased in MMP-9 KO compared with WT mice (15.2±12.6% versus 2.0±3.0%, P<0.002). Myocardial interferon-β1, interferon-, interleukin-6, interleukin-10, and macrophage inflammatory protein-1 expression was elevated in MMP-9 KO mice as measured by quantitative real-time polymerase chain reaction and ELISA. In contrast, MMP-8 KO mice had the same degree of cardiac injury, fibrosis, and viral infection as their WT counterparts.

Conclusions— During acute CVB3 infection, MMP-9 appears necessary to halt virus propagation in the heart, promote proper immune infiltration and remodeling, and preserve cardiac output.

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