PT  - JOURNAL ARTICLE
AU  - Zhou, Jian Ping
AU  - Lin, Ying Ni
AU  - Li, Ning
AU  - Sun, Xian Wen
AU  - Ding, Yong Jie
AU  - Yan, Ya Ru
AU  - Zhang, Liu
AU  - Li, Qing Yun
TI  - Angiotensin-(1–7) Rescues Chronic Intermittent Hypoxia-Aggravated Transforming Growth Factor-<em>β</em>–Mediated Airway Remodeling in Murine and Cellular Models of Asthma
AID  - 10.1124/jpet.120.000150
DP  - 2020 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 268--275
VI  - 375
IP  - 2
4099  - http://jpet.aspetjournals.org/content/375/2/268.short
4100  - http://jpet.aspetjournals.org/content/375/2/268.full
SO  - J Pharmacol Exp Ther2020 Nov 01; 375
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.