Soluble Fas, an inhibitor of apoptosis, gene therapy using adenovirus vector for ischemia-reperfusion injury

可溶性Fas，一种细胞凋亡抑制剂，利用腺病毒载体进行缺血再灌注损伤的基因治疗

• 批准号: 13670699
• 负责人: MINATOGUCHI Shinya
• 金额: $ 2.24万
• 依托单位: GIFU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670699/
• 关键词: sFas gene therapy; myocardial infarction; LV remodeling; heart failure; Fas; Fas Ligand system; Fasリガンド・システム

We examined potential therapeutic effects of soluble Fas (sFas), an inhibitor of apoptosis, on post-infarct left ventricular remodeling and heart failure. On the 3rd day of myocardial infarction (MI) of mice, adenovirus encoding sFas (Ad.CAG-sFas) was injected into the hindlimb muscle (1x10^9 pfu/mouse) to deliver sFas gene. As a control, adenovirus encoding LacZ gene was used. The treatment with sFas gene successfully suppressed apoptosis of granulation tissue cells, resulting in "a cell-rich scar tissue" at chronic stage (4 weeks later) in which blood vessels and myofibroblasts were abundant among fibrous tissue. The treatment greatly alleviated post-infarct left ventricular remodeling (based on improved echocardiogram and reduced heart to body weight ratio) and dysfunction (based on hemodynamic measurements). The results may imply a new therapeutic strategy against post-infarct heart failure, which is applicable even at subacute stage of MI.

我们研究了可溶性Fas（sFas），一种凋亡抑制剂，对梗死后左心室重构和心力衰竭的潜在治疗作用。在小鼠心肌梗死（MI）的第3天，将编码sFas的腺病毒（Ad.CAG-sFas）注射到后肢肌肉中（1 × 109 pfu/小鼠）以递送sFas基因。作为对照，使用编码LacZ基因的腺病毒。sFas基因治疗成功地抑制了肉芽组织细胞的凋亡，在慢性阶段（4周后）产生了“富含细胞的瘢痕组织”，其中在纤维组织中血管和肌成纤维细胞丰富。该治疗大大缓解了梗死后左心室重塑（基于超声心动图改善和心脏与体重比降低）和功能障碍（基于血液动力学测量）。这一结果可能意味着一种新的治疗策略，即使在亚急性期的心肌梗死后心力衰竭，这是适用的。

项目成果

Shinya Minatoguchi, Yoshihiro Uno, Tatsuya Kariya, Masazumi Arai, Ningyuan Wang, Kazuaki Hashimoto, Yoshio Nishida, Rumi Maruyama, Genzou Takemura, Takako Fujiwara, Hisayoshi Fujiwara: "Crosstalk among noradrenaline, adenosine and protein kinase C in the

Shinya Minatoguchi、Yoshihiro Uno、Tatsuya Kariya、Masazumi Arai、Ningyuan Wang、Kazuaki Hashimoto、Yoshio Nishida、Rumi Maruyama、Genzou Takemura、Takako Fujiwara、Hisayoshi Fujiwara：“去甲肾上腺素、腺苷和蛋白激酶 C 之间的串扰

Hayakawa K, Takemura G, Koda M, Kawase Y, Maruyama R, Li Y, Minatoguchi S, Fujiwara T, Fujiwara H.: "Sensitivity to apoptosis signal, clearance rate, and ultrastructure of fas ligand-induced apoptosis in vivo adult cardiac cells"Circulation. 105. 3039-45

Hayakawa K、Takemura G、Koda M、Kawase Y、Maruyama R、Li Y、Minatoguchi S、Fujiwara T、Fujiwara H.：“体内 fas 配体诱导的成体心肌细胞凋亡对凋亡信号的敏感性、清除率和超微结构

Hayakawa K et al.: "Sensitivity to apoptosis signal, clearance rate, and ultrastructure of fas ligand-induced apoptosis in in vivo adult cardiac cells"Circulation. 105. 3039-3045 (2002)

Hayakawa K等人：“体内成体心肌细胞中fas配体诱导的细胞凋亡对细胞凋亡信号、清除率和超微结构的敏感性”循环。

Masanori Kawasaki, Hisato Takatsu, Toshiyuki Noda, Keiji Sano, Yoko Ito, Kenji Hayakawa, Kunihiko Tsuchiya, Masazumi Arai, Kazuhiko Nishigaki, Genzou Takemura, Shinya Minatoguchi, Takako Fujiwara, Hisayoshi Fujiwara: "In Vivo Quantitative Tissue Character

Masanori Kawasaki、Hisato Takatsu、Toshiyuki Noda、Keiji Sano、Yoko Ito、Kenji Hayakawa、Kunihiko Tsuchiya、Masazumi Arai、Kazuhiko Nishigaki、Genzou Takemura、Shinya Minatoguchi、Takako Fujiwara、Hisayoshi Fujiwara：“体内定量组织特征

Kawasaki M et al.: "Noninvasive quantitative tissue characterization and two-dimensional color-coded map of human atherosclerotic lesion using ultrasound integrated backscatter. Comparoson between histology and integrated backcatter images"Journal of the

Kawasaki M 等人：“使用超声集成反向散射对人体动脉粥样硬化病变进行非侵入性定量组织表征和二维颜色编码图。组织学与集成反向散射图像之间的比较”Journal of the