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Serum–Glucocorticoid Regulated Kinase 1 Regulates Macrophage Recruitment and Activation Contributing to Monocrotaline-Induced Pulmonary Arterial Hypertension

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Abstract

Sustained inflammation is associated with pulmonary vascular remodeling and arterial hypertension (PAH). Serum–glucocorticoid regulated kinase 1 (SGK1) has been shown to participate in vascular remodeling, but its role in inflammation-associated PAH remains unknown. In this study, the importance of SGK1 expression and activation was investigated on monocrotaline (MCT)-induced PAH, an inflammation-associated experimental model of PAH used in mice and rats. The expression of SGK1 in the lungs of rats with MCT-induced PAH was significantly increased. Furthermore, SGK1 knockout mice were resistant to MCT-induced PAH and showed less elevation of right ventricular systolic pressure and right ventricular hypertrophy and showed reduced pulmonary vascular remodeling in response to MCT injection. Administering the SGK1 inhibitor, EMD638683, to rats also prevented the development of MCT-induced PAH. The expression of SGK1 was shown to take place primarily in alveolar macrophages. EMD638683 treatment suppressed macrophage infiltration and inhibited the proliferation of pulmonary arterial smooth muscle cells (PASMCs) in the lungs of rats with MCT-induced PAH. Co-culture of bone marrow-derived macrophages (BMDMs) from wild-type (WT) mice promoted proliferation of PASMC in vitro, whereas BMDMs from either SGK1 knockout mice or WT mice with EMD638683 treatment failed to induce this response. Collectively, the present results demonstrated that SGK1 is important to the regulation of macrophage activation that contributes to the development of PAH; thus, SGK1 may be a potential therapeutic target for the treatment of PAH.

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Acknowledgments

We would like to thank Dr. Shulan Qiu and Dr. Jing Zhang for analysis of the confocal laser-scanning microscope images and Dr. Tamsin Garrod from the University of Adelaide to edit the English language. This study was supported by from Chinese Ministry of Science and Technology (2012CB945104), the National Natural Science Foundation of China (81230006, 81130001), Program for Changjiang Scholars and Innovative Research Team in University (IRT1074), Beijing, collaborative innovative research center for cardiovascular diseases (PXM2013_014226_07_000088) and Open Project Program of Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders (2014HXFB02).

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Authors and Affiliations

  1. Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Xin Xi, Shuang Liu, Hongtao Shi, Min Yang, Yongfen Qi & Jie Du

  2. The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, 100029, China

    Xin Xi, Shuang Liu, Hongtao Shi, Min Yang, Yongfen Qi & Jie Du

  3. Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China

    Xin Xi, Shuang Liu, Hongtao Shi, Min Yang, Yongfen Qi & Jie Du

  4. State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The 1st Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Jian Wang

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Correspondence to Jie Du.

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Xi, X., Liu, S., Shi, H. et al. Serum–Glucocorticoid Regulated Kinase 1 Regulates Macrophage Recruitment and Activation Contributing to Monocrotaline-Induced Pulmonary Arterial Hypertension. Cardiovasc Toxicol 14, 368–378 (2014). https://doi.org/10.1007/s12012-014-9260-4

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