Acta Academiae Medicinae Sinica

Acta Academiae Medicinae Sinica

Acta Academiae Medicinae Sinica ›› 2017, Vol. 39 ›› Issue (1): 120-127.doi: 10.3881/j.issn.1000-503X.2017.01.020

• Orginal Article • Previous Articles     Next Articles

Effect of Bortezomib on Angiotensin Ⅱ-induced Abdominal Aortic Aneurysm in ApoE-/- Mice

Fangda LI1, Huihua LI2,3, Cui TIAN4, Hao NIE1, Yuehong ZHENG1()   

  1. 1Department of Vascular Surgery,PUMC Hospital,CAMS and PUMC,Beijing 100730,China
    2Department of Cardiology,Institute of Cardiovascular Diseases,First Affiliated Hospital of Dalian Medical University,Dalian,Liaoning 116011,China
    3Center for Prevention and Control of Non-communicable Chronic Diseases,School of Public Health,Dalian Medical University,Dalian,Liaoning 116044,China
    4Department of Physiology and Physiopathology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China
  • Received:2016-01-07 Online:2017-02-10 Published:2017-02-20
  • Supported by:
    Supported by the National Natural Sciences Foundation of China (81270390,81470586),the National Basic Research Program of China (973 Program)(2012CB517802),and the Chang Jiang Scholar Program

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.

Key words: abdominal aortic aneurysm, proteasome, bortezomib, inflammation, nuclear factor κ, B signaling

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