Baicalin attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A(2A) 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 effects. Moreover, we examined whether the inflammatory response was mediated by the A(2A) receptor (A(2A)R) 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(2A)R knockout (A(2A)R(−/−)) animals to chronic hypoxia, and we examined the effects of a 4-week treatment with baicalin or the A(2A)R agonist CGS21680 in these animals. Invasive hemodynamic parameters, the right ventricular hypertrophy index, pulmonary congestion, the pulmonary arterial remodeling index, blood gas parameters, A(2A)R expression, and the expression of SDF-1/CXCR4/PI3K/protein kinase B (PKB; AKT) signaling components were measured. RESULTS: Compared with WT mice, A(2A)R(−/−) 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(a)O(2)) and hydrogen ion concentration (pH). In the HPH model, A(2A)R(−/−) mice displayed increased CXCR4, SDF-1, phospho-PI3K, and phospho-AKT expression compared with WT mice. Treating WT and A(2A)R(−/−) 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(2A)R levels in WT lung tissue were enhanced by hypoxia and that baicalin up-regulated A(2A)R expression in WT hypoxic mice. CONCLUSIONS: Baicalin exerts protective effects against clinical HPH, which are partly mediated through enhanced A(2A)R activity and down-regulated SDF-1/CXCR4-induced PI3K/AKT signaling. Therefore, the A(2A)R may be a promising target for baicalin in treating HPH.