Abstract
Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease in the elderly. Activation of Notch1 pathway plays a critical role in the development of AAA, but the underlying mechanisms remain poorly understood. In the present study, we explored the mechanisms by which Notch1 activation regulates angiotensin II (Ang II)-induced AAA formation and evaluated the therapeutic potential of a new Notch γ-secretase inhibitor, dibenzazepine (DBZ), for the treatment of AAA. Apolipoprotein E knockout (Apo E−/−) mice infused for 4 weeks with Ang II (1000 ng/kg/min, IP) using osmotic mini-pumps were received an intraperitoneal injection of either vehicle or 1 mg/kg/d DBZ. Notch1 signaling was activated in AAA tissue from both Ang II-infused Apo E−/− mice and human undergoing AAA repair in vivo, with increased expression of Notch intracellular domain (NICD) and its target gene Hes1, and this effect was effectively blocked by DBZ. Moreover, infusion of Ang II markedly increased the incidence and severity of AAA in Apo E−/− mice. In contrast, inhibition of Notch activation by DBZ prevented AAA formation in vivo. Furthermore, DBZ markedly prevented Ang II-stimulated accumulation of macrophages and CD4+ T cells, and ERK-mediated angiogenesis, simultaneously reversed Th2 response, in vivo. In conclusion, these findings provide new insight into the multiple mechanisms of Notch signaling involved in AAA formation and suggest that γ-secretase inhibitor DBZ might be a novel therapeutic drug for treating AAAS.
Highlights
Abdominal aortic aneurysm (AAA) is a leading cause of sudden death in aging (> 65 years) men
To investigate the role of Notch signaling in the AAA formation, we first examined the expression of Notch intracellular domain (NICD) and its downstream effector Hes1 in the abdominal aorta of human AAA tissue or angiotensin II (Ang II)-infused Apo E-/mice
Immunofluorescent staining was performed in human AAA tissue with antibodies against Hes1 and α-smooth muscle-actin (α-SMA)
Summary
Abdominal aortic aneurysm (AAA) is a leading cause of sudden death in aging (> 65 years) men. Numerous mechanisms are known to contribute to aortic dilatation formation, but the unique pathways driving this process are incompletely understood. Several signaling pathways, including AMPK, ERK and Notch, have been proved to play a critical role in AAA formation [1,2]. The Notch family, including Notch 1-4, acts as receptors and is essential for cellular growth, differentiation, apoptosis and vessel formation. Genetic studies of mice have demonstrated an essential role of Notch signaling in vascular remodeling [4,5]. Hans et al demonstrate that Notch activation promotes AAA formation through macrophage-mediated inflammation [3]. The exact mechanisms by which Notch signaling contributes to the development of AAA remain to be explored
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