Baicalin attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A(2A) receptor-induced SDF-1/CXCR4/PI3K/AKT signaling.
Baicalin attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A(2A) receptor-induced SDF-1/CXCR4/PI3K/AKT signaling.
复制标题
黄芩苷通过腺苷 A(2A) 受体诱导的 SDF-1/CXCR4/PI3K/AKT 信号传导减轻慢性缺氧引起的肺动脉高压
DOI：
10.1186/s12929-017-0359-3
复制
发表时间：
2017-08-03
影响因子：
11
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Huang X;Wu P;Huang F;Xu M;Chen M;Huang K;Li GP;Xu M;Yao D;Wang L
黄芩苷是黄芩提取物中重要的黄酮类化合物，具有多种药理作用。本研究旨在探讨黄芩苷对慢性缺氧性肺动脉高压（PAH）的作用及其机制。此外，我们还研究了炎症反应是否由A2 A受体（A2 AR）和基质细胞衍生因子-1（SDF-1）/C-X-C趋化因子受体4型（CXCR 4）诱导的磷脂酰肌醇-3-激酶（PI 3 K）信号转导介导。我们通过将野生型（WT）和A2 AR敲除（A2 AR −/−）动物置于慢性缺氧中建立了缺氧诱导的肺动脉高压（HPH）小鼠模型，并检查了黄芩苷或A2 AR激动剂CGS 21680对这些动物进行4周治疗的影响。检测有创血流动力学指标、右心室肥厚指数、肺充血指数、肺动脉重构指数、血气指标、A2 AR表达、SDF-1/CXCR 4/PI 3 K/蛋白激酶B（PKB; AKT）信号成分的表达。与WT小鼠相比，A2 AR −/−小鼠在平均颈动脉压（mCAP）无改变的情况下，右心室收缩压（RVSP）、右心室与左心室加室间隔[RV/（LV + S）]比值、RV重量与体重（RV/BW）比值和肺湿重与体重（Lung/BW）比值升高。这些变化伴随着肺动脉壁面积和厚度的增加以及动脉血氧分压（PaO 2）和氢离子浓度（pH）的降低。在HPH模型中，与WT小鼠相比，A2 AR −/−小鼠显示CXCR 4、SDF-1、磷酸化PI 3 K和磷酸化AKT表达增加。用黄芩苷或CGS 21680处理WT和A2 AR −/− HPH小鼠可减弱缺氧诱导的RVSP、RV/（LV + S）和肺/BW增加以及肺动脉重塑。此外，黄芩苷或CGS 21680单独可逆转缺氧诱导的CXCR 4、SDF-1、磷酸化PI 3 K和磷酸化AKT表达的增加。黄芩苷可改善缺氧4周引起的低氧血症。最后，我们发现缺氧可增强WT肺组织中A2 AR的表达，黄芩苷可上调WT缺氧小鼠A2 AR的表达。黄芩苷对临床HPH具有保护作用，这部分是通过增强A2 AR活性和下调SDF-1/CXCR 4诱导的PI 3 K/AKT信号转导介导的。因此，A2 AR可能是黄芩苷治疗HPH的一个有希望的靶点。
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 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. We 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. Compared 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. Baicalin 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.
登录
查看更多内容
影响因子：
3
作者：
Garat CV;Crossno JT Jr;Sullivan TM;Reusch JE;Klemm DJ
通讯作者：
Klemm DJ
影响因子：
20.1
作者：
Young KC;Torres E;Hatzistergos KE;Hehre D;Suguihara C;Hare JM
通讯作者：
Hare JM
黄芩苷对缺氧性肺动脉高压大鼠肺动脉Ⅰ型胶原和Ⅲ型胶原表达的影响
影响因子：
5.4
作者：
Liu, Panpan;Yan, Shuangquan;Huang, Xiaoying
通讯作者：
Huang, Xiaoying
影响因子：
1.7
作者：
Xu, M. H.;Gong, Y. S.;Wang, X. T.
通讯作者：
Wang, X. T.
影响因子：
3.7
作者：
Chen JB;Yang YH;Lee WC;Liou CW;Lin TK;Chung YH;Chuang LY;Yang CH;Chang HW
通讯作者：
Chang HW