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Angiotensin II downregulates catalase expression and activity in vascular adventitial fibroblasts through an AT1R/ERK1/2-dependent pathway

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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.

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Abbreviations

Ang II:

Angiotensin II

AT1R:

Angiotensin II type 1 receptor

α-SMA:

α-Smooth muscle actin

CAT:

Catalase

ERK1/2:

Extracellular signal-regulated kinase 1/2

GPx:

Glutathione peroxidase

H2O2 :

Hydrogen peroxide

MAPKs:

Mitogen-activated protein kinases

PI3-kinase:

Phosphoinositide-3-kinase

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

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Acknowledgments

This research was supported by the Grants from Shanghai Municipal Health Bureau Youth Research Projects (No. 2010Y55) and the International Non-Governmental Cooperation Projects from the Shanghai Science and Technical Committee (No. 09410706900). The authors are grateful to Dr. Tianqing Peng, the University of Western Ontario, for his technical assistance.

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Authors and Affiliations

  1. Department of Geriatrics, RenJi Hospital, Shanghai Jiao Tong University School of Medicine, No. 145, Shandong Middle Road, Shanghai, 200001, China

    Weiwei Yang, Jia Zhang, Haiya Wang & Ningyuan Fang

  2. Joint Laboratory of Vascular Biology of Health Science Center and Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Pingjin Gao

  3. Department of Pathology, University of Western Ontario, London, ON, Canada

    Manpreet Singh

  4. Division of Cardiology, Zhoushan People’s Hospital, Zhoushan, Zhejiang, 316000, China

    Kai Shen

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  1. Weiwei Yang
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  2. Jia Zhang
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  6. Kai Shen
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Correspondence to Ningyuan Fang.

Additional information

Weiwei Yang and Jia Zhang equally contributed to this work.

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11010_2011_915_MOESM1_ESM.tif

Supplementary Figures Effect of Ang II on activities and expressions of SOD and GPx in adventitial fibroblasts. Cells were stimulated with Ang II (10−7 M) for 0, 0.5, 2, 6, 12, 24, or 48 h, or with different concentrations (0, 10−8, 10−7, 10−6, 10−5 M) of Ang II for 24 h. The activities of SOD (S1 and S2) and GPx (S3 and S4) as well as protein and mRNA levels of Cu/Zn-SOD (S5, S6 and S7), Mn-SOD (S5, S8 and S9) and GPx (S5, S10 and S11) were analyzed by Western blotting and RT–PCR. Data are means±SD from three independent experiments

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Yang, W., Zhang, J., Wang, H. et al. Angiotensin II downregulates catalase expression and activity in vascular adventitial fibroblasts through an AT1R/ERK1/2-dependent pathway. Mol Cell Biochem 358, 21–29 (2011). https://doi.org/10.1007/s11010-011-0915-1

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  • DOI: https://doi.org/10.1007/s11010-011-0915-1

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