| First Author | Cheung C | Year | 2008 |
| Journal | Circulation | Volume | 117 |
| Issue | 12 | Pages | 1574-82 |
| PubMed ID | 18332263 | Mgi Jnum | J:148442 |
| Mgi Id | MGI:3844795 | Doi | 10.1161/CIRCULATIONAHA.107.733238 |
| Citation | Cheung C, et al. (2008) Ablation of matrix metalloproteinase-9 increases severity of viral myocarditis in mice. Circulation 117(12):1574-82 |
| abstractText | 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-beta1, interferon-gamma, interleukin-6, interleukin-10, and macrophage inflammatory protein-1alpha 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. |
