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

Abstract

BackgroundBaicalin, 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 A2A receptor (A2AR) 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.MethodsWe established a hypoxia-induced pulmonary hypertension (HPH) mouse model by subjecting wild-type (WT) and A2AR knockout (A2AR−/−) animals to chronic hypoxia, and we examined the effects of a 4-week treatment with baicalin or the A2AR agonist CGS21680 in these animals. Invasive hemodynamic parameters, the right ventricular hypertrophy index, pulmonary congestion, the pulmonary arterial remodeling index, blood gas parameters, A2AR expression, and the expression of SDF-1/CXCR4/PI3K/protein kinase B (PKB; AKT) signaling components were measured.ResultsCompared with WT mice, A2AR−/− 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 (PaO2) and hydrogen ion concentration (pH). In the HPH model, A2AR−/− mice displayed increased CXCR4, SDF-1, phospho-PI3K, and phospho-AKT expression compared with WT mice. Treating WT and A2AR−/− 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 A2AR levels in WT lung tissue were enhanced by hypoxia and that baicalin up-regulated A2AR expression in WT hypoxic mice.ConclusionsBaicalin exerts protective effects against clinical HPH, which are partly mediated through enhanced A2AR activity and down-regulated SDF-1/CXCR4-induced PI3K/AKT signaling. Therefore, the A2AR may be a promising target for baicalin in treating HPH.

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

“…Bleomycin has been reported to suppress pulmonary fibrosis through the A2A receptor and the SDF‐1/CXCR4 signaling pathway 32 . Besides, adenosine A2A receptor has been proved to mediate the SDF‐1/CXCR4/PI3K/AKT signaling pathways to regulate the progression of pulmonary hypertension 33 . However, the relationship among adenosine A2A receptor, SDF‐1 and CXCR4 remains unclear.…”

“…32 Besides, adenosine A2A receptor has been proved to mediate the SDF-1/ CXCR4/PI3K/AKT signaling pathways to regulate the progression of pulmonary hypertension. 33 However, the relationship among adenosine A2A receptor, SDF-1 and CXCR4 remains unclear. In our study, we firstly revealed the correlation among the adenosine A2A receptor, SDF-1 and CXCR4 in the lung-to-brain metastatic process.…”

Synergistic therapeutic effects of Duzhong Jiangya Tablets and amlodipine besylate combination in spontaneously hypertensive rats using 1H‐NMR‐ and MS‐based metabolomics

“…The structures are shown in Figure 1. Some studies have shown that these ingredients influence the cardiovascular system (Cao et al, 2017;Gao, Chen, Liang, Xie, & Chen, 2015;Huang et al, 2017;Olaleye, Crown, Akinmoladun, & Akindahunsi, 2014).…”

In vitro and in vivo activities of flavonoids – apigenin, baicalin, chrysin, scutellarin – in regulation of hypertension – a review for their possible effects in pregnancy-induced hypertension

“…In other study [54], carried out in the same model of PH, showed that 2% baicalin solution downregulated the p38 mitogen-activated protein kinase MAPK/MMP-9 pathway and expression levels of MMP-9. Huang et al [51] observed additionally that baicalin (60 mg/kg i.p.) attenuated chronic hypoxia-induced PH via adenosine A2A receptor-induced SDF-1/CXCR4/PI3K/AKT signaling.…”

“…Baicalin has been widely studied in several in vitro and in vivo models and showed many activities such as: anti-viral [42], anti-oxidative via several pathways [43], neuroprotective and enhancin cognitive functions [44,45], anti-inflammatory [46], anti-cancer [47,48], and hepatoprotection [49]. In recent years, many studies showed anti-hypertensive properties of baicalin [46,[50][51][52][53][54][55][56][57][58][59][60], and also cardioprotective [50], antiplatelet, anticoagulant, and profibrinolytic activities [61].…”