VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

• Published in: Journal of the American Heart Association Vol. 7; no. 17; p. e010069
• Main Authors: Peng, Huihui, Zhang, Kai, Liu, Zhaoya, Xu, Qian, You, Baiyang, Li, Chan, Cao, Jing, Zhou, Honghua, Li, Xiaohui, Chen, Jia, Cheng, Guangjie, Shi, Ruizheng, Zhang, Guogang
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 04.09.2018; Wiley
• Subjects: abdominal aortic aneurysm; Aged; Animals; Aorta, Abdominal - cytology; Aortic Aneurysm, Abdominal - metabolism; Aortic Aneurysm, Abdominal - physiopathology; Cell Movement; Cell Proliferation; Disease Models, Animal; Female; Hemeproteins - drug effects; Hemeproteins - metabolism; Humans; hydrogen peroxide; Hydrogen Peroxide - pharmacology; Hypochlorous Acid - pharmacology; Kruppel-Like Transcription Factors - metabolism; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 2 - metabolism; Mice; Middle Aged; Muscle Contraction; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - physiopathology; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - metabolism; Original Research; Oxidants - pharmacology; oxidative stress; Peroxidases - drug effects; Peroxidases - metabolism; Phenotype; Reactive Oxygen Species; abdominal aortic aneurysm; oxidative stress; hydrogen peroxide
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.118.010069

Background Hydrogen peroxide (H O ) is a critical molecular signal in the development of abdominal aortic aneurysm ( AAA ) formation. Vascular peroxidase 1 ( VPO 1) catalyzes the production of hypochlorous acid ( HOC l) from H O and significantly enhances oxidative stress. The switch from a contractile phenotype to a synthetic one in vascular smooth muscle cells ( VSMC s) is driven by reactive oxygen species and is recognized as an early and important event in AAA formation. This study aims to determine if VPO 1 plays a critical role in the development of AAA by regulating VSMC phenotypic switch. Methods and Results VPO 1 is upregulated in human and elastase-induced mouse aneurysmal tissues compared with healthy control tissues. Additionally, KLF 4, a nuclear transcriptional factor, is upregulated in aneurysmatic tissues along with a concomitant downregulation of differentiated smooth muscle cell markers and an increase of synthetic phenotypic markers, indicating VSMC phenotypic switch in these diseased tissues. In cultured VSMC s from rat abdominal aorta, H O treatment significantly increases VPO 1 expression and HOC l levels as well as VSMC phenotypic switch. In support of these findings, depletion of VPO 1 significantly attenuates the effects of H O and HOC l treatment. Furthermore, HOC l treatment promotes VSMC phenotypic switch and ERK 1/2 phosphorylation. Pretreatment with U0126 (a specific inhibitor of ERK 1/2) significantly attenuates HOC l-induced VSMC phenotypic switch. Conclusions Our results demonstrate that VPO 1 modulates VSMC phenotypic switch through the H O / VPO 1/ HOC l/ ERK 1/2 signaling pathway and plays a key role in the development of AAA . Our findings also implicate VPO 1 as a novel signaling node that mediates VSMC phenotypic switch and plays a key role in the development of AAA . Clinical Trial Registration URL : www.chictr.org.cn . Unique identifier: Chi CTR 1800016922.