炎症
腹主动脉瘤
巨噬细胞
医学
主动脉瘤
内科学
动脉瘤
主动脉
化学
外科
生物化学
体外
作者
Chetan P. Hans,Sara N. Koenig,Nianyuan Huang,Jeeyun Cheng,Susana Beceiro,Anuradha Guggilam,Helena Kuivaniemi,Santiago Partida-Sánchez,Vidu Garg
标识
DOI:10.1161/atvbaha.112.254219
摘要
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.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.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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