RT Journal Article SR Electronic T1 Angiotensin-(1–7) Rescues Chronic Intermittent Hypoxia-Aggravated Transforming Growth Factor-β–Mediated Airway Remodeling in Murine and Cellular Models of Asthma JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 268 OP 275 DO 10.1124/jpet.120.000150 VO 375 IS 2 A1 Zhou, Jian Ping A1 Lin, Ying Ni A1 Li, Ning A1 Sun, Xian Wen A1 Ding, Yong Jie A1 Yan, Ya Ru A1 Zhang, Liu A1 Li, Qing Yun YR 2020 UL http://jpet.aspetjournals.org/content/375/2/268.abstract AB 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.