Cheng Zhang1, Dan Chen1, Eithne Margaret Maguire2, Shiping He2, Jiangyong Chen2,3, Weiwei An2, Mei Yang4, Tayyab Adeel Afzal2, Le Anh Luong2, Li Zhang4, Han Lei5, Qingchen Wu1, Qingzhong Xiao2,6,7. 1. Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing 400016, Yuzhong District, China. 2. Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. 3. Department of Cardiothoracic Surgery, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China. 4. Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China. 5. Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing 400016, Yuzhong District, China. 6. Key Laboratory of Cardiovascular Diseases, The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao Town, Guangzhou, Guangdong 511436, Panyu District, China. 7. Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao Town, Guangzhou, Guangdong 511436, Panyu District, China.
Abstract
AIMS: To investigate the role of chromobox protein homolog 3 (Cbx3) in vascular smooth muscle cell (VSMC) proliferation, migration, and neointima formation following vascular injury. METHODS AND RESULTS: Overexpression of Cbx3 led to a significant increase in VSMC contractile gene expression and VSMC apoptosis as well as a dramatic decrease in collagen gene expression, VSMC proliferation, and migration. Meanwhile, the opposite was observed following inhibition of endogenous Cbx3. Luciferase activity assays revealed that Notch signalling, but neither β-catenin nor NF-κB signalling, is regulated by Cbx3 in VSMCs, and among the four Notch receptors, Notch3 is selectively down-regulated by Cbx3 through a transcriptional repression mechanism. Notch3 gene activation recapitulates the effects of Cbx3 knockdown on VSMC proliferation and migration. Consequently, the inhibitory effects of Cbx3 over-expression on VSMC proliferation and migration were reversed by Notch3 gene reactivation. In a model of vascular damage by carotid wire injury, we observed that Cbx3 expression was dramatically down-regulated in the injured arteries. Local ectopic over-expression of Cbx3 in the injured arteries significantly inhibited Notch3 expression, thereby reducing VSMCs proliferation and causing an overall decrease in neointima formation. Additionally, injury-induced neointimal SMC hyperplasia was significantly reduced by aortic inhibition of Notch3. Importantly, a decreased expression level of Cbx3, but an increased expression level of Notch3, was observed in human femoral arteries with atherosclerotic lesions. CONCLUSION: Cbx3 modulates VSMC contractile and collagen gene expression, as well as VSMC proliferation, migration, and apoptosis via a Notch3 pathway, and plays an important role in controlling injury-induced neointima formation. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: To investigate the role of chromobox protein homolog 3 (Cbx3) in vascular smooth muscle cell (VSMC) proliferation, migration, and neointima formation following vascular injury. METHODS AND RESULTS: Overexpression of Cbx3 led to a significant increase in VSMC contractile gene expression and VSMC apoptosis as well as a dramatic decrease in collagen gene expression, VSMC proliferation, and migration. Meanwhile, the opposite was observed following inhibition of endogenous Cbx3. Luciferase activity assays revealed that Notch signalling, but neither β-catenin nor NF-κB signalling, is regulated by Cbx3 in VSMCs, and among the four Notch receptors, Notch3 is selectively down-regulated by Cbx3 through a transcriptional repression mechanism. Notch3 gene activation recapitulates the effects of Cbx3 knockdown on VSMC proliferation and migration. Consequently, the inhibitory effects of Cbx3 over-expression on VSMC proliferation and migration were reversed by Notch3 gene reactivation. In a model of vascular damage by carotid wire injury, we observed that Cbx3 expression was dramatically down-regulated in the injured arteries. Local ectopic over-expression of Cbx3 in the injured arteries significantly inhibited Notch3 expression, thereby reducing VSMCs proliferation and causing an overall decrease in neointima formation. Additionally, injury-induced neointimal SMC hyperplasia was significantly reduced by aortic inhibition of Notch3. Importantly, a decreased expression level of Cbx3, but an increased expression level of Notch3, was observed in human femoral arteries with atherosclerotic lesions. CONCLUSION: Cbx3 modulates VSMC contractile and collagen gene expression, as well as VSMC proliferation, migration, and apoptosis via a Notch3 pathway, and plays an important role in controlling injury-induced neointima formation. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Guanmei Wen; Weiwei An; Jiangyong Chen; Eithne M Maguire; Qishan Chen; Feng Yang; Stuart W A Pearce; Maria Kyriakides; Li Zhang; Shu Ye; Sussan Nourshargh; Qingzhong Xiao Journal: J Am Heart Assoc Date: 2018-02-08 Impact factor: 5.501
Authors: Weiwei An; Le A Luong; Neil P Bowden; Mei Yang; Wei Wu; Xinmiao Zhou; Chenxin Liu; Kaiyuan Niu; Jun Luo; Cheng Zhang; Xiaolei Sun; Robin Poston; Li Zhang; Paul C Evans; Qingzhong Xiao Journal: Cardiovasc Res Date: 2022-01-29 Impact factor: 13.081
Authors: Malwina Prater; Russell S Hamilton; Hong Wa Yung; Andrew M Sharkey; Paul Robson; N Erlyani Abd Hamid; Eric Jauniaux; D Stephen Charnock-Jones; Graham J Burton; Tereza Cindrova-Davies Journal: Biol Open Date: 2021-06-08 Impact factor: 2.422