Wnt11 gene therapy with adeno-associated virus 9 improves the survival of mice with myocarditis induced by coxsackievirus B3 through the suppression of the inflammatory reaction
Wnt11 gene therapy with adeno-associated virus 9 improves the survival of mice with myocarditis induced by coxsackievirus B3 through the suppression of the inflammatory reaction
复制标题
DOI：
10.1016/j.yjmcc.2015.04.009
复制
发表时间：
2015-07-01
影响因子：
5
通讯作者：
Murohara, Toyoaki
中科院分区：
文献类型：
--
作者：
Aoyama, Yutaka;Kobayashi, Koichi;Murohara, Toyoaki
wnt信号通路在发育和许多疾病中起着重要作用。最近的一些报道表明，非典型的Wnt蛋白有助于成年动物的炎症反应。然而，Wnt蛋白对病毒诱导的心肌炎的影响尚未被探索。在这里，我们研究了Wnt 1 1蛋白在柯萨奇病毒B3（CVB 3）诱导的心肌炎模型中的作用，使用重组腺相关病毒9（rAAV 9）。使用雄性BALB/c小鼠检查Wnt 11基因治疗对CVB 3诱导的心肌炎模型的作用。在腹膜内施用CVB 3之前2周，小鼠接受rAAV 9-Wntll或rAAV 9-LacZ的单次静脉内注射。静脉注射rAAV 9载体导致有效、持久和相对心脏特异性的转基因表达。经rAAV 9-Wnt 11处理的小鼠的存活率显著高于经rAAV 9-LacZ处理的小鼠（87.5%对54.1%，P < 0.05）。Wnt 11表达还可减少炎性细胞浸润、心肌坏死，抑制炎性细胞因子mRNA表达。这是第一份报告表明Wntl I表达改善了患有CVB 3诱导的心肌炎的小鼠的存活率。AAV 9介导的Wnt 11基因治疗通过抑制炎性细胞浸润和炎性细胞因子的基因表达，对心脏功能产生有益作用，并增加患有CVB 3诱导的心肌炎的小鼠的存活率。(C)2015年，作者。爱思唯尔有限公司出版
The wnt signaling pathway plays important roles in development and in many diseases. Recently several reports suggest that non-canonical Wnt proteins contribute to the inflammatory response in adult animals. However, the effects of Wnt proteins on virus-induced myocarditis have not been explored. Here, we investigated the effect of Wnt1 1 protein in a model of myocarditis induced by coxsackievirus B3 (CVB3) using recombinant adeno-associated virus 9 (rAAV9). The effect of Wnt1 1 gene therapy on a CVB3-induced myocarditis model was examined using male BALB/c mice. Mice received a single intravenous injection of either rAAV9-Wnt1 1 or rAAV9-LacZ 2 weeks before intraperitoneal administration of CVB3. Intravenous injection of the rAAV9 vector resulted in efficient, durable, and relatively cardiac-specific transgene expression. Survival was significantly greater among rAAV9-Wnt11 treated mice than among mice treated with rAAV9-LacZ (87.5% vs. 54.1%, P < 0.05). Wnt11 expression also reduced the infiltration of inflammatory cells, necrosis of the myocardium, and suppressed the mRNA expression of inflammatory cytokines. This is the first report to show that Wntl I expression improves the survival of mice with CVB3-induced myocarditis. AAV9-mediated Wnt11 gene therapy produces beneficial effects on cardiac function and increases the survival of mice with CVB3-induced myocarditis through the suppression of both infiltration of inflammatory cells and gene expression of inflammatory cytokines. (C) 2015 The Authors. Published by Elsevier Ltd.