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.


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.
Cheung
Caroline
C
Department of Pathology and Laboratory Medicine, The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital/Providence Health Care Research Institute, Vancouver, British Columbia, Canada V6Z 1Y6.
Marchant
David
D
Walker
Elizabeth K-Y
EK
Luo
Zongshu
Z
Zhang
Jingchun
J
Yanagawa
Bobby
B
Rahmani
Maziar
M
Cox
Jennifer
J
Overall
Christopher
C
Senior
Robert M
RM
Luo
Honglin
H
McManus
Bruce M
BM
D000818:Animals; D029822:Enterovirus B, Human; D004769:Enterovirus Infections; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000276:immunology* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D014779:Virus Replication
D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9