Ablation of matrix metalloproteinase-9 increases severity of viral myocarditis in mice

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-beta 1, interferon-gamma, interleukin-6, interleukin- 10, and macrophage inflammatory protein-1 alpha 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.