The ubiquitin-activating enzyme E1 as a novel therapeutic target for the treatment of restenosis

• Published in: Atherosclerosis Vol. 247; pp. 142 - 153
• Main Authors: Qin, Zhexue, Cui, Bin, Jin, Jun, Song, Mingbao, Zhou, Baoshang, Guo, Hongfeng, Qian, Dehui, He, Yongming, Huang, Lan
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.04.2016
• Subjects: Adenoviridae - genetics; Animals; Benzoates - pharmacology; Cardiovascular; Carotid Arteries - drug effects; Carotid Arteries - enzymology; Carotid Arteries - pathology; Carotid Artery Injuries - enzymology; Carotid Artery Injuries - genetics; Carotid Artery Injuries - pathology; Carotid Artery Injuries - therapy; Carotid Stenosis - enzymology; Carotid Stenosis - genetics; Carotid Stenosis - pathology; Carotid Stenosis - prevention & control; Cell Cycle - drug effects; Cell Cycle Proteins - metabolism; Cell Proliferation - drug effects; Cells, Cultured; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Furans - pharmacology; Genetic Vectors; Inflammation; Inflammation Mediators - metabolism; Male; Neointima; Pyrazoles - pharmacology; Rats, Sprague-Dawley; Recurrence; Restenosis; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RNAi Therapeutics - methods; Signal Transduction - drug effects; Time Factors; Transfection; Ubiquitin-activating enzyme E1; Ubiquitin-Activating Enzymes - antagonists & inhibitors; Ubiquitin-Activating Enzymes - genetics; Ubiquitin-Activating Enzymes - metabolism; Vascular injury; Ubiquitin-activating enzyme E1; Restenosis; Inflammation; Vascular injury
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2016.02.016

Abstract Aims The ubiquitin-activating enzyme E1 (UBA1, E1), the apex of the ubiquitin proteasome pathway, plays a critical role in protein degradation and in pathological processes. Whether UBA1 participates the development of vascular restenosis remains unknown. This study aims to determine the role of UBA1 in the development of balloon injury induced neointimal formation. Methods and results Immunostaining and western blots were used to examine the expression of the ubiquitinated protein in the injured carotid after angioplasty. Higher levels of ubiquitinated protein were observed in the neointima. Local delivery of potent chemical UBA1 inhibitor PYR-41 (100 μM) and UBA1 shRNA lentivirus both resulted in a substantial decrease in intimal hyperplasia at 2 weeks and 4 weeks after balloon injury. UBA1 inhibition also reduced Ki-67 positive cell percentage and inflammatory response in the carotid artery wall. We further determined that in vitro UBA1 inhibition was able to ameliorate TNF-α-induced nuclear factor-kappa B (NF-κB) activation by reducing IκB degradation in vascular smooth muscle cells (VSMCs). UBA1 inhibition also led to the accumulation of short-lived proteins such as p53, p21 and c-jun, which may account for the UBA1 inhibition-induced cell cycle delay. Thus, VSMCs proliferation was blocked. Conclusions UBA1 inhibition effectively suppresses neointimal thickening through its anti-proliferative and anti-inflammatory effects. Our results provide further evidence that the ubiquitin-proteasome system is a potential new target for the prevention of vascular restenosis.