Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo
Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo
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DOI：
10.1152/ajpheart.00777.2002
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发表时间：
2003-02-01
影响因子：
4.8
通讯作者：
Kitsis, RN
中科院分区：
文献类型：
--
作者：
Lee, P;Sata, M;Kitsis, RN
Fas是一种广泛表达的细胞表面受体，当被其配体（FasL）激活时可启动细胞凋亡。尽管心肌细胞上的Fas丰度在多种病理刺激下增加，但缺乏支持其在心脏病发病机制中作用的直接证据。此外，存在争议，甚至Fas激活是否诱导心肌细胞凋亡。在这项研究中，我们表明，腺病毒过度表达FasL，但不是β-半乳糖苷酶，结果在原代新生心肌细胞和完整的成年大鼠心肌细胞的培养显着的凋亡。FasL对肌细胞的杀伤是一种特异性事件，因为它不发生在缺乏功能性Fas的lpr（淋巴增生）小鼠中。为了评估Fas途径对体内心肌梗死（MI）的贡献，对lpr小鼠进行30分钟的缺血，随后进行24小时的再灌注。与野生型小鼠相比，lpr小鼠的梗死面积小62.3%，心肌细胞凋亡减少63.8%。这些数据提供了直接的证据表明，激活Fas可以诱导心肌细胞凋亡，Fas是一个关键的调解人，由于缺血再灌注心肌梗死在体内。
Fas is a widely expressed cell surface receptor that can initiate apoptosis when activated by its ligand (FasL). Whereas Fas abundance on cardiac myocytes increases in response to multiple pathological stimuli, direct evidence supporting its role in the pathogenesis of heart disease is lacking. Moreover, controversy exists even as to whether Fas activation induces apoptosis in cardiac myocytes. In this study, we show that adenoviral overexpression of FasL, but not beta-galactosidase, results in marked apoptosis both in cultures of primary neonatal cardiac myocytes and in the myocardium of intact adult rats. Myocyte killing by FasL is a specific event, because it does not occur in lpr (lymphoproliferative) mice that lack functional Fas. To assess the contribution of the Fas pathway to myocardial infarction (MI) in vivo, lpr mice were subjected to 30 min of ischemia followed by 24 h of reperfusion. Compared with wild-type mice, lpr mice exhibited infarcts that were 62.3% smaller with 63.8% less myocyte apoptosis. These data provide direct evidence that activation of Fas can induce apoptosis in cardiac myocytes and that Fas is a critical mediator of MI due to ischemia-reperfusion in vivo.