title: Effect of Bortezomib on Angiotensin Ⅱ-induced Abdominal Aortic Aneurysm in ApoE-/-Mice.
abstract: Objective To investigate the role of proteasome inhibitor bortezomib (BTZ) in inflammatory response in abdominal aortic aneurysm (AAA) formation induced by angiotensin Ⅱ (Ang Ⅱ). Methods Ang Ⅱ-induced ApoE-/-mice AAA models were established. Forty male ApoE-/-mice (8-10-week-old) were randomly and equally divided into four groups:Sham group,BTZ group,Ang Ⅱ group,and Ang Ⅱ+BTZ group.HE staining,immunohistochemical staining,and flow cytometry were used to analyze the inflammatory response. Real-time quantitative polymerase chain reaction (qPCR) was used to analyze the mRNA expression of intercellular cell adhesion molecule-1 (ICAM-1). Western blotting was used to analyze the activation of nuclear factor κB signaling (NF-κB). Results The mean maximum suprarenal aortic diameter (Dmax) of Sham group,BTZ group,Ang Ⅱ group,and Ang Ⅱ+BTZ group were (1.00±0.01),(0.99±0.01),(1.50±0.13),and (1.20±0.04)mm,respectively (F=8.959,P=0.000). The Dmax of Ang Ⅱ group was significantly larger than those of Sham group (P=0.000) and Ang Ⅱ+BTZ group (P=0.015). The incidence of AAA in Ang Ⅱ group,Ang Ⅱ+BTZ group,and Sham group were 60%,17%,and 0,respectively. HE staining revealed that the abdominal aortic wall thickening was more severe in Ang Ⅱ group than in Sham group and Ang Ⅱ+BTZ group,similar with the infiltration of inflammatory cells. Immunohistochemical staining demonstrated that the CD3+T lymphocyte count was significantly higher in Ang Ⅱ group than in Sham group (107.9±15.9 vs. 0,P=0.000) and Ang Ⅱ+BTZ group (107.9±15.9 vs. 0.8±0.5,P=0.000). Flow cytometry also demonstrated that the proportion of the CD3+T lymphocytes of the Ang Ⅱ group [(13.50±0.69)%] was significantly higher than that in the Ang Ⅱ+BTZ group [(10.40±0.78)%] at week 1 (t=3.009,P=0.040),and the proportion of the CD3+T lymphocytes of the Ang Ⅱ group [(22.70±0.93)%] was significantly higher than that in the Ang Ⅱ+BTZ group [(15.10±0.97)%] at week 4 (t=5.654,P=0.005). The qPCR analysis showed that the mRNA expression of ICAM-1 was significantly up-regulated in Ang Ⅱ group than in Sham group (1.93±0.54 vs. 1.00±0.15,P=0.011) and Ang Ⅱ+BTZ group (1.93±0.54 vs. 0.83±0.08,P=0.009). Western blot analysis showed a lower phosphorylation level of inhibitor of NF-κB in the Ang Ⅱ group compared with the Sham group or Ang Ⅱ+BTZ group,accompanied with an increased phosphorylation level of p65. Conclusion Proteasome inhibitor BTZ can attenuate AAA formation partially by regulating T lymphocytes infiltration through regulating the mRNA expression of ICAM-1 regulated by the activation of NF-κB signaling pathway.
authors.affiliation: Department of Vascular Surgery,PUMC Hospital,CAMS and PUMC,Beijing 100730,China.
authors.forename: Fangda
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Cardiology,Institute of Cardiovascular Diseases,First Affiliated Hospital of Dalian Medical University,Dalian,Liaoning 116011,China ;Center for Prevention and Control of Non-communicable Chronic Diseases,School of Public Health,Dalian Medical University,Dalian,Liaoning 116044,China.
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Physiology and Physiopathology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China.
authors.forename: Cui
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Vascular Surgery,PUMC Hospital,CAMS and PUMC,Beijing 100730,China.
authors.forename: Hao
authors.initials: H
authors.lastname: Nie
authors.affiliation: Department of Vascular Surgery,PUMC Hospital,CAMS and PUMC,Beijing 100730,China.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000188:drug therapy*; D001057:Apolipoproteins E / Q000235:genetics; D000069286:Bortezomib / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011897:Random Allocation; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D001057:Apolipoproteins E; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D000069286:Bortezomib