Anti-Fas Gene Therapy Prevents Doxorubicin-Induced Acute Cardiotoxicity through Mechanisms Independent of Apoptosis
Anti-Fas Gene Therapy Prevents Doxorubicin-Induced Acute Cardiotoxicity through Mechanisms Independent of Apoptosis
复制标题
DOI：
10.2353/ajpath.2010.090222
复制
发表时间：
2010-02-01
影响因子：
6
通讯作者：
Minatoguchi, Shinya
中科院分区：
文献类型：
--
作者：
Miyata, Shusaku;Takemura, Genzou;Minatoguchi, Shinya
Fas信号的激活是阿霉素心脏毒性的关键介质，其涉及心肌细胞凋亡和心肌炎症。本研究用阿霉素诱导小鼠急性心脏毒性，同时肌肉注射Fas/Fas配体相互作用抑制剂--编码小鼠可溶性Fas（sFas）基因的腺病毒载体（Ad.CAG-sFas）。两周后，LacZ治疗对照组的左心室扩张和功能障碍明显，但sFas治疗组两者均显著减轻。原位缺口末端标记阳性率在两组中相似，尽管电子显微镜显示心肌细胞变性，但未检测到凋亡结构特征和半胱氨酸天冬氨酸蛋白酶的激活，表明凋亡在该模型中的作用不显著。相反，sFas治疗逆转了阿霉素诱导的加塔-4下调，并减弱了肌球蛋白重链和肌钙蛋白I的泛素化，以保护这些肌节蛋白。此外，阿霉素诱导的显著的白细胞浸润、纤维化和心肌氧化损伤，所有这些都在很大程度上被sFas处理逆转。sFas处理还抑制阿霉素诱导的p53过表达、c-Jun N-末端激酶的磷酸化、c-Jun和核因子-κ B的抑制剂，以及环加氧酶-2和单核细胞趋化蛋白-1的产生，它恢复了细胞外信号调节激酶的激活。因此，sFas基因治疗可以防止阿霉素诱导的急性心脏毒性的进展，同时减轻由Fas信号传导引起的心肌细胞变性、炎症、纤维化和氧化损伤。(Am J Pathol 2010，176：687-698; DOL：10.2353/ajpath.2010.090222）
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-kappa B, 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. (Am J Pathol 2010, 176:687-698; DOL: 10.2353/ajpath.2010.090222)