title: 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.
abstract: 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 Wnt11 protein in a model of myocarditis induced by coxsackievirus B3 (CVB3) using recombinant adeno-associated virus 9 (rAAV9). The effect of Wnt11 gene therapy on a CVB3-induced myocarditis model was examined using male BALB/c mice. Mice received a single intravenous injection of either rAAV9-Wnt11 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 Wnt11 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.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Aoyama
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466, Japan. Electronic address: k-koba@med.nagoya-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Morishita
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D003384:Coxsackievirus Infections / Q000628:therapy* / Q000821:virology; D016207:Cytokines / Q000378:metabolism; D000229:Dependovirus / Q000378:metabolism*; D004770:Enterovirus / Q000502:physiology*; D015870:Gene Expression; D015316:Genetic Therapy; D007249:Inflammation / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000517:prevention & control / Q000628:therapy* / Q000821:virology*; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D009504:Neutrophils / Q000473:pathology; D009928:Organ Specificity; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000473:pathology; D014709:Vero Cells; D051153:Wnt Proteins / Q000235:genetics / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D051153:Wnt Proteins; C508957:Wnt11 protein, mouse
keywords: Adeno-associated virus 9; Inflammation; Viral myocarditis; Wnt11