title: Angiotensin II downregulates catalase expression and activity in vascular adventitial fibroblasts through an AT1R/ERK1/2-dependent pathway.
abstract: Angiotensin II (Ang II) plays a profound regulatory effect on NADPH oxidase and the functional features of vascular adventitial fibroblasts, but its role in antioxidant enzyme defense remains unclear. This study investigated the effect of Ang II on expressions and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in adventitial fibroblasts and the possible mechanism involved. Ang II decreased the expression and activity of CAT in a dose- and time-dependent manner, but not that of SOD and GPx. The effects were abolished by the angiotensin II type 1 receptor (AT1R) blocker losartan and AT1R small-interfering RNA (siRNA). Incubation with polyethylene glycol-CAT prevented the Ang II-induced effects on reactive oxygen species (ROS) generation and myofibroblast differentiation. Moreover, Ang II rapidly induced phosphorylation of ERK1/2, which was reversed by losartan and AT1R siRNA. Pharmacological blockade of ERK1/2 improved Ang II-induced decrease in CAT protein expression. These in vitro results indicate that Ang II induces ERK1/2 activation, contributing to the downregulation of CAT as well as promoting oxidative stress and adventitial fibroblast phenotypic differentiation in an AT1R-mediated manner.
authors.affiliation: Department of Geriatrics, RenJi Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Yang
authors.forename: Jia
authors.initials: J
authors.lastname: Zhang
authors.forename: Haiya
authors.initials: H
authors.lastname: Wang
authors.forename: Pingjin
authors.initials: P
authors.lastname: Gao
authors.forename: Manpreet
authors.initials: M
authors.lastname: Singh
authors.forename: Kai
authors.initials: K
authors.lastname: Shen
authors.forename: Ningyuan
authors.initials: N
authors.lastname: Fang
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000166:cytology*; D002374:Catalase / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D003239:Connective Tissue Cells / Q000166:cytology; D015536:Down-Regulation / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011092:Polyethylene Glycols / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*
chemical_list: D000804:Angiotensin II; D000975:Antioxidants; D002374:Catalase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011092:Polyethylene Glycols; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; C070295:catalase-polyethylene glycol