Tumor necrosis factor-α is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction
Tumor necrosis factor-α is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction
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DOI：
10.1152/ajpheart.00166.2007
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发表时间：
2007-07-01
影响因子：
4.8
通讯作者：
Sunagawa, Kenji
中科院分区：
文献类型：
--
作者：
Monden, Yoshiya;Kubota, Toru;Sunagawa, Kenji
受损心肌中诱导的肿瘤坏死因子（TNF）-α被认为具有心脏毒性。 TNF-α 通过结合两种不同的受体：R1 (p55) 和 R2 (p75) 来启动其生物效应。尽管 TNF-α 已被证明通过 R1 介导的途径具有心脏毒性，但人们对 R2 介导的途径在心肌梗塞 (MI) 中的作用知之甚少。我们通过结扎左冠状动脉在 R1 敲除 (R1KO)、R2KO 和野生型 (WT) 小鼠中产生 MI。连接后4周进行功能、组织学和生化分析。尽管 WT、R1KO 和 R2KO 小鼠的梗塞面积没有差异，但 R1KO 小鼠的 MI 后存活率显着提高，而 R2KO 小鼠则没有。 R1KO 显着改善 MI 后的收缩功能障碍，而 R2KO 显着加剧心室扩张和功能障碍。 R2KO 小鼠中非梗塞心肌的心肌细胞肥大和间质纤维化加剧，但 R1KO 小鼠中则没有。 R1 的表达不受 MI 影响，在 R1KO 小鼠中无效，但在 R2KO 小鼠中显着上调。相比之下，R2的表达在R1KO小鼠中不受影响，而R2的表达在R2KO小鼠中被MI显着上调并被消除。同时，MI后非梗死心肌中TNF-α的表达显着上调，但不受R1KO或R2KO的影响。然而，MI后显着上调的IL-6、IL-1β、转化生长因子-β和单核细胞趋化蛋白-1的转录水平在R1KO小鼠中显着下调。相比之下，R2KO 小鼠中 IL-6 和 IL-1 β 的转录水平显着进一步上调。在 MI 小鼠模型中，TNF-α 通过 R1 产生毒性，并通过 R2 发挥保护作用。选择性阻断 R1 可能是 MI 的候选治疗干预措施。
Tumor necrosis factor (TNF)-alpha induced in damaged myocardium has been considered to be cardiotoxic. TNF-alpha initiates its biological effects by binding two distinct receptors: R1 (p55) and R2 (p75). Although TNF-alpha has been shown to be cardiotoxic via R1-mediated pathways, little is known about the roles of R2-mediated pathways in myocardial infarction (MI). We created MI in R1 knockout (R1KO), R2KO, and wild-type (WT) mice by ligating the left coronary artery. Functional, histological, and biochemical analyses were performed 4 wk after ligation. Although infarct size was not different among WT, R1KO, and R2KO mice, post-MI survival was significantly improved in R1KO but not R2KO mice. R1KO significantly ameliorated contractile dysfunction after MI, whereas R2KO significantly exaggerated ventricular dilatation and dysfunction. Myocyte hypertrophy and interstitial fibrosis in noninfarct myocardium was exacerbated in R2KO but not in R1KO mice. Expression of R1, which was not affected by MI and was nullified in R1KO mice, was significantly upregulated in R2KO mice. In contrast, expression of R2, which was significantly upregulated by MI and was nullified in R2KO mice, was unaffected in R1KO mice. Meanwhile, TNF-alpha expression, which was significantly upregulated in noninfarct myocardium after MI, was not affected by R1KO or R2KO. However, transcript levels of IL-6, IL-1 beta, transforming growth factor-beta, and monocyte chemotactic protein-1, which were significantly upregulated after MI, were significantly downregulated in R1KO mice. In contrast, transcript levels of IL-6 and IL-1 beta were significantly further upregulated in R2KO mice. TNF-alpha is toxic via R1 and protective via R2 in a murine model of MI. Selective blockade of R1 may be a candidate therapeutic intervention for MI.