Baicalin attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2A receptor-induced SDF-1/CXCR4/PI3K/AKT signaling

Background Baicalin, an important flavonoid in Scutellaria baicalensis Georgi extracts, exerts a variety of pharmacological effects. In this study, we explored the effects of baicalin on chronic hypoxia-induced pulmonary arterial hypertension (PAH) and investigated the mechanism underlying these eff...

Full description

Saved in:
Bibliographic Details
Published inJournal of biomedical science Vol. 24; no. 1; p. 52
Main Authors Huang, Xiaoying, Wu, Peiliang, Huang, Feifei, Xu, Min, Chen, Mayun, Huang, Kate, Li, Guo-ping, Xu, Manhuan, Yao, Dan, Wang, Liangxing
Format Journal Article
LanguageEnglish
Published Basel BioMed Central Ltd 03.08.2017
BioMed Central
BMC
Subjects
Online AccessGet full text

Cover

Loading…
More Information
Summary:Background Baicalin, an important flavonoid in Scutellaria baicalensis Georgi extracts, exerts a variety of pharmacological effects. In this study, we explored the effects of baicalin on chronic hypoxia-induced pulmonary arterial hypertension (PAH) and investigated the mechanism underlying these effects. Moreover, we examined whether the inflammatory response was mediated by the A.sub.2A receptor (A.sub.2AR) and stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-induced phosphatidyl inositol-3-kinase (PI3K) signaling in vivo. Methods We established a hypoxia-induced pulmonary hypertension (HPH) mouse model by subjecting wild-type (WT) and A.sub.2AR knockout (A.sub.2AR.sup.-/-) animals to chronic hypoxia, and we examined the effects of a 4-week treatment with baicalin or the A.sub.2AR agonist CGS21680 in these animals. Invasive hemodynamic parameters, the right ventricular hypertrophy index, pulmonary congestion, the pulmonary arterial remodeling index, blood gas parameters, A.sub.2AR expression, and the expression of SDF-1/CXCR4/PI3K/protein kinase B (PKB; AKT) signaling components were measured. Results Compared with WT mice, A.sub.2AR.sup.-/- mice exhibited increased right ventricular systolic pressure (RVSP), right ventricle-to-left ventricle plus septum [RV/(LV + S)] ratio, RV weight-to-body weight (RV/BW) ratio, and lung wet weight-to-body weight (Lung/BW) ratio in the absence of an altered mean carotid arterial pressure (mCAP). These changes were accompanied by increases in pulmonary artery wall area and thickness and reductions in arterial oxygen pressure (P.sub.aO.sub.2) and hydrogen ion concentration (pH). In the HPH model, A.sub.2AR.sup.-/- mice displayed increased CXCR4, SDF-1, phospho-PI3K, and phospho-AKT expression compared with WT mice. Treating WT and A.sub.2AR.sup.-/- HPH mice with baicalin or CGS21680 attenuated the hypoxia-induced increases in RVSP, RV/(LV + S) and Lung/BW, as well as pulmonary arterial remodeling. Additionally, baicalin or CGS21680 alone could reverse the hypoxia-induced increases in CXCR4, SDF-1, phospho-PI3K, and phospho-AKT expression. Moreover, baicalin improved the hypoxemia induced by 4 weeks of hypoxia. Finally, we found that A.sub.2AR levels in WT lung tissue were enhanced by hypoxia and that baicalin up-regulated A.sub.2AR expression in WT hypoxic mice. Conclusions Baicalin exerts protective effects against clinical HPH, which are partly mediated through enhanced A.sub.2AR activity and down-regulated SDF-1/CXCR4-induced PI3K/AKT signaling. Therefore, the A.sub.2AR may be a promising target for baicalin in treating HPH. Keywords: Baicalin, Pulmonary arterial hypertension, Receptor, Adenosine A.sub.2A, SDF-1, CXCR4
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1423-0127
1021-7770
1423-0127
DOI:10.1186/s12929-017-0359-3