Inhibition of Proteasome Activity by Low-dose Bortezomib Attenuates Angiotensin II-induced Abdominal Aortic Aneurysm in Apo E(-/-) Mice.
Abdominal aortic aneurysm (AAA) is a leading cause of sudden death in aged people. Activation of ubiquitin proteasome system (UPS) plays a critical role in the protein quality control and various diseases. However, the functional role of UPS in AAA formation remains unclear. In this study, we found that the proteasome activities and subunit expressions in AAA tissues from human and angiotensin II (Ang II)-infused apolipoprotein E knockout (Apo E(-/-)) mice were significantly increased. To investigate the effect of proteasome activation on the AAA formation, Apo E(-/-) mice were cotreated with bortezomib (BTZ) (a proteasome inhibitor, 50 μg/kg, 2 times per week) and Ang II (1000 ng/kg/min) up to 28 days. Ang II infusion significantly increased the incidence and severity of AAA in Apo E(-/-) mice, whereas BTZ treatment markedly inhibited proteasome activities and prevented AAA formation. Furthermore, BTZ treatment significantly reduced the inflammation, inhibited the metal matrix metalloprotease activity, and reversed the phenotypic SMC modulation in AAA tissue. In conclusion, these results provide a new evidence that proteasome activation plays a critical role in AAA formation through multiple mechanisms, and suggest that BTZ might be a novel therapeutic target for treatment of AAA formation.
Department of Vascular Surgery, Peking Union Medical College Hospital, Beijing, PR China.
Hualiang
H
Ren
Department of Vascular Surgery, Peking Union Medical College Hospital, Beijing, PR China.
Fangda
F
Li
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, PR China.
Cui
C
Tian
Department of Vascular Surgery, Peking Union Medical College Hospital, Beijing, PR China.
Hao
H
Nie
Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
Lei
L
Wang
Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.|Center for Prevention and Control of Non-communicable Chronic Diseases, School of Public Health, Dalian Medical University, Dalian 116044, PR China.
Hui-Hua
HH
Li
Department of Vascular Surgery, Peking Union Medical College Hospital, Beijing, PR China.
Yuehong
Y
Zheng
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism*; D001057:Apolipoproteins E / Q000378:metabolism*; D000069286:Bortezomib / Q000494:pharmacology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D061988:Proteasome Inhibitors / Q000494:pharmacology*
D001057:Apolipoproteins E; D061988:Proteasome Inhibitors; D000804:Angiotensin II; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex