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Research ArticleDrug Discovery and Translational Medicine

Angiotensin-(1–7) Rescues Chronic Intermittent Hypoxia-Aggravated Transforming Growth Factor-β–Mediated Airway Remodeling in Murine and Cellular Models of Asthma

Jian Ping Zhou, Ying Ni Lin, Ning Li, Xian Wen Sun, Yong Jie Ding, Ya Ru Yan, Liu Zhang and Qing Yun Li
Journal of Pharmacology and Experimental Therapeutics November 2020, 375 (2) 268-275; DOI: https://doi.org/10.1124/jpet.120.000150
Jian Ping Zhou
Department of Respiratory and Critical Care Medicine, Ruijin Hospital and Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Ying Ni Lin
Department of Respiratory and Critical Care Medicine, Ruijin Hospital and Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Ning Li
Department of Respiratory and Critical Care Medicine, Ruijin Hospital and Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Xian Wen Sun
Department of Respiratory and Critical Care Medicine, Ruijin Hospital and Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Yong Jie Ding
Department of Respiratory and Critical Care Medicine, Ruijin Hospital and Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Ya Ru Yan
Department of Respiratory and Critical Care Medicine, Ruijin Hospital and Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Liu Zhang
Department of Respiratory and Critical Care Medicine, Ruijin Hospital and Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Qing Yun Li
Department of Respiratory and Critical Care Medicine, Ruijin Hospital and Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Abstract

Renin-angiotensin system (RAS) is involved in TGF-β–mediated epithelial-to-mesenchymal transition (EMT) and is responsible for airway remodeling in refractory asthma. Obstructive sleep apnea (OSA), which affects RAS activity, is a risk factor for refractory asthma. We aimed to investigate how chronic intermittent hypoxia (IH), the main pathophysiology of OSA, exacerbates asthma and whether Ang-(1–7) protects against chronic IH–induced airway remodeling in asthma. We exposed ovalbumin (OVA)-challenged asthma mice to chronic IH and observed that chronic IH aggravated airway inflammation and collagen deposit in OVA-challenged mice. Compared with the OVA group, the OVA + chronic IH group had a lower expression level of epithelial marker E-cadherin and higher expression levels of mesenchymal markers α-smooth muscle actin and collagen IV in airway epithelia, accompanied with activation of TGF-β/Smad pathway. These changes were reversed by the administration of Ang-(1–7). Consistently, Ang-(1–7) mitigated chronic IH–induced activation of TGF-β–mediated EMT in lipopolysaccharide-treated bronchial epithelial cells in a dose-dependent manner, which was blocked by Ang-(1–7)–specific Mas receptor antagonist A779. Taken together, Ang-(1–7) rescued chronic IH–aggravated TGF-β–mediated EMT to suppress airway remodeling, implying that RAS activity is involved in the mechanisms of OSA-related airway dysfunction in asthma.

SIGNIFICANCE STATEMENT OSA is a risk factor for refractory asthma. In this study, we aimed to explore the mechanisms of how OSA exacerbates refractory asthma. We found that chronic IH induces TGF-β–mediated EMT and aggravates airway collagen deposit. We also found that Ang-(1–7) erased the aggravation of TGF-β–mediated EMT and epithelial fibrosis upon chronic IH exposure. These findings provided new insights that the ACE2/Ang-(1–7)/Mas axis might be considered as a potential therapeutic target for patients with asthma and OSA.

Footnotes

    • Received June 5, 2020.
    • Accepted August 25, 2020.
  • ↵1 J.P.Z. and Y.N.L. contributed equally to this article as co-first authors.

  • We would like to acknowledge funding grants from the National Natural Science Foundation of China [81700085, 81700084], National Key R&D Program of China [2018YFC1311900], and Shanghai Key Discipline for Respiratory Disease [2017ZZ02014] and support from Innovative research team of high-level local universities in Shanghai.

  • All authors disclose no conflicts of interest.

  • https://doi.org/10.1124/jpet.120.000150.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 375 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 2
1 Nov 2020
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Research ArticleDrug Discovery and Translational Medicine

Ang-(1–7) Reduces EMT in Asthma Combined with OSA

Jian Ping Zhou, Ying Ni Lin, Ning Li, Xian Wen Sun, Yong Jie Ding, Ya Ru Yan, Liu Zhang and Qing Yun Li
Journal of Pharmacology and Experimental Therapeutics November 1, 2020, 375 (2) 268-275; DOI: https://doi.org/10.1124/jpet.120.000150

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Research ArticleDrug Discovery and Translational Medicine

Ang-(1–7) Reduces EMT in Asthma Combined with OSA

Jian Ping Zhou, Ying Ni Lin, Ning Li, Xian Wen Sun, Yong Jie Ding, Ya Ru Yan, Liu Zhang and Qing Yun Li
Journal of Pharmacology and Experimental Therapeutics November 1, 2020, 375 (2) 268-275; DOI: https://doi.org/10.1124/jpet.120.000150
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