title: Anti-Fas gene therapy prevents doxorubicin-induced acute cardiotoxicity through mechanisms independent of apoptosis.
abstract: Activation of Fas signaling is a key mediator of doxorubicin cardiotoxicity, which involves both cardiomyocyte apoptosis and myocardial inflammation. In this study, acute cardiotoxicity was induced in mice by doxorubicin, and some mice simultaneously received an intramuscular injection of adenoviral vector encoding mouse soluble Fas (sFas) gene (Ad.CAG-sFas), an inhibitor of Fas/Fas ligand interaction. Two weeks later, left ventricular dilatation and dysfunction were apparent in the LacZ-treated control group, but both were significantly mitigated in the sFas-treated group. The in situ nick-end labeling-positive rate were similar in the two groups, and although electron microscopy revealed cardiomyocyte degeneration, no apoptotic structural features and no activation of caspases were detected, suggesting an insignificant role of apoptosis in this model. Instead, sFas treatment reversed doxorubicin-induced down-regulation of GATA-4 and attenuated ubiquitination of myosin heavy chain and troponin I to preserve these sarcomeric proteins. In addition, doxorubicin-induced significant leukocyte infiltration, fibrosis, and oxidative damage to the myocardium, all of which were largely reversed by sFas treatment. sFas treatment also suppressed doxorubicin-induced p53 overexpression, phosphorylation of c-Jun N-terminal kinase, c-Jun, and inhibitor of nuclear factor-kappaB, as well as production of cyclooxygenase-2 and monocyte chemoattractant protein-1, and it restored extracellular signal-regulated kinase activation. Therefore, sFas gene therapy prevents the progression of doxorubicin-induced acute cardiotoxicity, with accompanying attenuation of the cardiomyocyte degeneration, inflammation, fibrosis, and oxidative damage caused by Fas signaling.
authors.affiliation: Division of Cardiology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Shusaku
authors.initials: S
authors.lastname: Miyata
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Kosai
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Masayasu
authors.initials: M
authors.lastname: Esaki
authors.forename: Longhu
authors.initials: L
authors.lastname: Li
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kanamori
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Kazuko
authors.initials: K
authors.lastname: Goto
authors.forename: Akiko
authors.initials: A
authors.lastname: Tsujimoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takeyama
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ohno
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishigaki
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage / Q000235:genetics; D004317:Doxorubicin; D004452:Echocardiography; D004719:Endomyocardial Fibrosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D015316:Genetic Therapy / Q000379:methods*; D006331:Heart Diseases / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007763:Lac Operon; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D012995:Solubility; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D019014:fas Receptor; D004317:Doxorubicin