Effect of Bortezomib on Angiotensin Ⅱ-induced Abdominal Aortic Aneurysm in ApoEMice.
10.3881/j.issn.1000-503X.2017.01.020
- Author:
Fangda LI
1
;
Huihua LI
2
;
Cui TIAN
3
;
Hao NIE
1
;
Yuehong ZHENG
1
Author Information
1. Department of Vascular Surgery,PUMC Hospital,CAMS and PUMC,Beijing 100730,China.
2. Department of Cardiology,Institute of Cardiovascular Diseases,First Affiliated Hospital of Dalian Medical University,Dalian,Liaoning 116011,China
3. Department of Physiology and Physiopathology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China.
- Publication Type:Journal Article
- MeSH:
Angiotensin II;
adverse effects;
Animals;
Aortic Aneurysm, Abdominal;
chemically induced;
drug therapy;
Apolipoproteins E;
genetics;
Bortezomib;
pharmacology;
Intercellular Adhesion Molecule-1;
metabolism;
Male;
Mice;
Mice, Inbred C57BL;
Mice, Knockout;
NF-kappa B;
metabolism;
Phosphorylation;
Proteasome Inhibitors;
pharmacology;
Random Allocation;
Signal Transduction;
T-Lymphocytes;
cytology
- From:
Acta Academiae Medicinae Sinicae
2017;39(1):120-127
- CountryChina
- Language:English
-
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 ApoEmice AAA models were established. Forty male ApoEmice (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 CD3T 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 CD3T 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 CD3T 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.
