Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha
Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha
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DOI：
10.1161/01.res.81.4.627
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发表时间：
1997-10-01
影响因子：
20.1
通讯作者：
Feldman, AM
中科院分区：
文献类型：
--
作者：
Kubota, T;McTiernan, CF;Feldman, AM
衰竭的人类心脏表达肿瘤坏死因子-α (TNF-α)。但其病理生理学意义尚不清楚。我们之前报道过，小鼠心脏中 TNF-α 的强烈过度表达会导致致命的心肌炎。在这项研究中，我们通过保留 TNF-α cDNA 中的不稳定序列来修饰转基因，以减少 TNF-α 的产生。表达由鼠α-肌球蛋白重链启动子驱动。使用这种修饰的构建体使我们能够建立小鼠转基因系（TG）。 TG 后代在第 6、12 和 24 周时进行检查。所有这些都显示出明显更高的心脏重量与体重之比。 Northern印迹分析证实了转基因在心脏中的表达，酶联免疫吸附测定证实了TNF-α蛋白的存在。 TG 心脏显示轻度、弥漫性淋巴组织细胞间质炎症浸润。存在心肌细胞坏死和凋亡，但并不丰富。磁共振成像显示TG心脏明显扩张，射血分数降低。尽管左心室 dP/dt(max) 在基线时没有差异，但其对异丙肾上腺素的反应在 TG 中显着减弱。心房钠尿因子在TG心室中表达。一组TG自然死亡，随后的尸检显示心脏异常扩张、肺部重量增加和胸腔积液，表明他们死于充血性心力衰竭。 6个月时的累积死亡率为23%。总之，过度表达 TNF-α 的小鼠再现了充血性心力衰竭的表型。这提供了一种新的模型来阐明这种细胞因子在充血性心力衰竭发展中的作用。
The failing human heart expresses tumor necrosis factor-alpha (TNF-alpha). However, its pathophysiological significance is not clear. We previously reported that robust overexpression of TNF-alpha in the murine heart causes lethal myocarditis. In this study, we modified the transgene to reduce the production of TNF-alpha by preserving the destabilizing sequence in TNF-alpha cDNA. Expression was driven by the murine alpha-myosin heavy chain promoter. Use of this modified construct allowed us to establish a murine transgenic line (TG). TG offspring were examined at 6, 12, and 24 weeks. All showed a significantly higher heart weight-to-body weight ratio. Northern blot analysis confirmed the expression of transgene in the heart, and enzyme-linked immunosorbent assay demonstrated the presence of TNF-alpha protein. The TG heart demonstrated a mild, diffuse, lymphohistiocytic interstitial inflammatory infiltrate. Cardiomyocyte necrosis and apoptosis were present but not abundant. Magnetic resonance imaging showed that the TG heart was significantly dilated with reduced ejection fraction. Although the left ventricular dP/dt(max) was not different at baseline, its responsiveness to isoproterenol was significantly blunted in TG. Atrial natriuretic factor was expressed in the TG ventricle. A group of TG died spontaneously, and subsequent autopsies revealed exceptional dilatation of the heart, increased lung weight, and pleural effusion, suggesting that they died of congestive heart failure. The cumulative mortality rate at 6 months was 23%. In conclusion, the mouse overexpressing TNF-alpha recapitulated the phenotype of congestive heart failure. This provides a novel model to elucidate the role of this cytokine in the development of congestive heart failure.