title: Notch γ-secretase inhibitor dibenzazepine attenuates angiotensin II-induced abdominal aortic aneurysm in ApoE knockout mice by multiple mechanisms.
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.
authors.affiliation: Department of Vascular Surgery, Peking Union Medical Hospital, Beijing, China.
authors.forename: Yue-Hong
authors.initials: YH
authors.lastname: Zheng
authors.affiliation: Department of Vascular Surgery, Peking Union Medical Hospital, Beijing, China.
authors.forename: Fang-Da
authors.initials: FD
authors.lastname: Li
authors.affiliation: Department of Physiology and Physiopathology, Beijing AnZhen Hospital the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance, School of Basic Medical Sciences, Capital Medical University, Beijing, China; Beijing Institute of Heart, Lung and Blood vessel Diseases, Beijing, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Vascular Surgery, Peking Union Medical Hospital, Beijing, China.
authors.forename: Hua-Liang
authors.initials: HL
authors.lastname: Ren
authors.affiliation: Department of Physiology and Physiopathology, Beijing AnZhen Hospital the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance, School of Basic Medical Sciences, Capital Medical University, Beijing, China; Beijing Institute of Heart, Lung and Blood vessel Diseases, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Physiology and Physiopathology, Beijing AnZhen Hospital the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance, School of Basic Medical Sciences, Capital Medical University, Beijing, China; Beijing Institute of Heart, Lung and Blood vessel Diseases, Beijing, China.
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced* / Q000188:drug therapy* / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D003984:Dibenzazepines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D003984:Dibenzazepines; D051881:Receptor, Notch1; D000804:Angiotensin II; D053829:Amyloid Precursor Protein Secretases; C527817:dibenzazepine