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ATV Biol:抑制Notch 1路径或可减小腹部主动脉瘤的恶化

来源:生物谷 2012-10-25 23:07

2012年10月25日 讯 /生物谷BIOON/ --10月18日,刊登在国际杂志Arteriosclerosis, Thrombosis,and Vascular Biology上的一篇研究报告中,来自国立儿童医院的研究者揭示了,一个跟癌症及心血管疾病相关的基因或许是引发主动脉瘤的一个诱因,当然其或许可以帮助研究者早日开发出主动脉瘤的新型疗法。这项研究首次揭示了Notch 1信号在小鼠和人类腹部主动脉瘤中是处于激活状态的。

主动脉是机体中较大的血管,当腹部血管的主动脉血管壁处于膨胀状态时,就会引发腹主动脉瘤(Abdominal aortic aneurysm,AAA),其是主动脉微动脉瘤的一种常见形式。AAA是美国人死亡的一个主要原因,尤其是65岁以上的老年人,该疾病和吸烟、高血压以及高血脂相关。

炎症是AAA的一个主要标志,Notch 1基因参与了人类机体发育的许多环节,有研究表明,其信号路径在许多炎性疾病中是处于激活状态的。Notch 1信号是炎症反应的明显调节子,然而其在AAA发病中的分子机制却并不清楚。

为了测定Notch 1信号在AAA发病过程中所扮演的角色,研究者从患病小鼠模型以及接受治疗的患者体内取出了腹主动脉的活体组织,并对其进行了实验研究。研究者首次揭示了Notch 1途径在小鼠模型和患者中是处于激活状态的。随后研究者检测了Notch 1信号在高血压素II诱导的AAA小鼠模型中所扮演的角色,发现Notch 1路径是处于抑制状态的。

研究结果显示,Notch 1信号在AAA相关的炎性反应中扮演了一个重要的参与者的角色,Notch 1特异性抑制剂的疗法或许是一种治疗动脉瘤发展的潜在疗法。后期研究中,研究者需要深入研究来揭示AAA炎性因子在发病中的特殊作用。(生物谷Bioon.com)

编译自:Gene Linked to Inflammation in the Aorta May Contribute to Abdominal Aortic Aneurysm

Inhibition of Notch1 Signaling Reduces Abdominal Aortic Aneurysm in Mice by Attenuating Macrophage-Mediated Inflammation

Chetan P. Hans, Sara N. Koenig, Nianyuan Huang, Jeeyun Cheng, Susana Beceiro, Anuradha Guggilam, Helena Kuivaniemi, Santiago Partida-Sánchez, Vidu Garg

Objective—Activation of inflammatory pathways plays a critical role in the development of abdominal aortic aneurysms (AAA). Notch1 signaling is a significant regulator of the inflammatory response; however, its role in AAA is unknown. Methods and Results—In an angiotensin II–induced mouse model of AAA, activation of Notch1 signaling was observed in the aortic aneurysmal tissue of Apoe−/− mice, and a similar activation of Notch1 was observed in aneurysms of humans undergoing AAA repair. Notch1 haploinsufficiency significantly reduced the incidence of AAA in Apoe−/− mice in response to angiotensin II. Reconstitution of bone marrow–derived cells from Notch1+/−;Apoe−/− mice (donor) in lethally irradiated Apoe−/− mice (recipient) decreased the occurrence of aneurysm. Flow cytometry and immunohistochemistry demonstrated that Notch1 haploinsufficiency prevented the influx of inflammatory macrophages at the aneurysmal site by causing defects in macrophage migration and proliferation. In addition, there was an overall reduction in the inflammatory burden in the aorta of the Notch1+/−;Apoe−/− mice compared with the Apoe−/− mice. Last, pharmacological inhibition of Notch1 signaling also prevented AAA formation and progression in Apoe−/− mice. Conclusion—Our data suggest that decreased levels of Notch1 protect against the formation of AAA by preventing macrophage recruitment and attenuating the inflammatory response in the aorta.

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