Ablation of matrix metalloproteinase-9 increases severity of viral myocarditis in mice
Ablation of matrix metalloproteinase-9 increases severity of viral myocarditis in mice
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DOI：
10.1161/circulationaha.107.733238
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发表时间：
2008-03-25
期刊：
影响因子：
37.8
通讯作者：
McManus, Bruce M.
中科院分区：
文献类型：
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作者：
Cheung, Caroline;Marchant, David;McManus, Bruce M.
背景-柯萨奇病毒B3（CVB 3）引起人类心肌炎，可导致心脏损伤、适应不良重构和心力衰竭。基质金属蛋白酶（MMP）-8和-9已被确定在病毒感染的心肌，但他们的具体作用和潜在的作用机制是未知的。对于第一次，我们研究了严重的CVB 3诱导的心肌炎在MMP-8和MMP-9缺陷migration.Methods和结果-CVB 3感染的MMP-8和MMP-9敲除（KO）小鼠和相应的野生型（WT）小鼠被安乐死，并在感染后9天收获。MMP-2，-8，12，和-13和组织抑制剂的MMPs的表达进行了评估，通过酶谱法或免疫印迹收获的心脏，并进行原位杂交检测活动性感染。感染的MMP-9 KO小鼠具有比WT小鼠更大的心肌损伤和感染灶，尽管相似的胰腺感染。与WT小鼠相比，MMP-9 KO小鼠的纤维化增加（10.6 +/-2.7% vs 7.1 +/-2.6%，P = 0.04）、病毒滴度增加以及心输出量减少明显，分别通过天狼星红染色、空斑试验和超声心动图进行评估。与WT小鼠相比，MMP-9 KO中的免疫浸润也大大增加（15.2 +/- 12.6%对2.0 +/-3.0%，P < 0.002）。通过定量实时聚合酶链反应和ELISA测定，MMP-9 KO小鼠心肌干扰素-β 1、干扰素-γ、白细胞介素-6、白细胞介素-10和巨噬细胞炎性蛋白-1 α表达升高。相比之下，MMP-8基因敲除小鼠有相同程度的心脏损伤，纤维化和病毒感染作为他们的WT counter.Conclusions -在急性CVB 3感染，MMP-9出现必要停止病毒在心脏中的传播，促进适当的免疫浸润和重塑，并保存心输出量。
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.