摘要
目的基于网络药理学探讨清心解瘀颗粒(QXJYG)抗动脉粥样硬化(AS)的药效学及其调控机制。方法通过网络药理学挖掘QXJYG抗AS的关键靶点和信号通路。采用高脂喂养合并腹腔注射维生素D3的方式构建AS大鼠模型,将造模成功后的30只大鼠随机分为模型组、阿托伐他汀组(13.15 mg·kg^(-1)·d^(-1))、低剂量组(0.99 g·kg^(-1)·d^(-1))、中剂量组(1.98 g·kg^(-1)·d^(-1))、高剂量组(3.96 g·kg^(-1)·d^(-1)),每组6只;另外将6只SD大鼠给予正常饮食作为对照组。实验动物干预8周后,通过小动物超声检测大鼠腹主动脉血管内径、血管壁厚度、脉冲波传播速度、搏动指数,通过HE染色检测大鼠腹主动脉病理形态,通过全自动生化仪检测每组大鼠的血脂水平,通过ELISA检测试剂盒测定血清中AngⅡ、ET-1、TXA2、PGI2、ox-LDL含量。采用免疫组化法检测大鼠腹主动脉中LOX-1、PPARγ、RXRα、p-P65、VCAM-1、ICAM-1蛋白的表达。结果与正常组相比,模型组的腹主动脉血管壁厚度、脉冲波传播速度、搏动指数升高(P<0.05),血管内径减小(P<0.05),且平滑肌细胞增生、排列紊乱,TC、LDL-C、AngⅡ、ET-1、TXA2含量显著升高(P<0.05),HDL-C、PGI2含量显著下降(P<0.05)。与模型组相比,QXJYG和阿托伐他汀干预后,显著降低腹主动脉血管壁厚度、脉冲波传播速度、搏动指数(P<0.05),增大血管内径(P<0.05),减轻平滑肌细胞排列紊乱情况,显著降低TC、LDL-C,AngⅡ、ET-1、TXA2(P<0.05),显著升高HDL-C、PGI2含量(P<0.05),通过网络药理学预测发现QXJYG可能通过调控脂质,PPAR和NF-κB等信号通路发挥抗AS的作用。与正常组相比,模型组的ox-LDL含量、LOX-1、p-P65、VCAM-1、ICAM-1蛋白表达水平显著升高(P<0.05),PPARγ、RXRα蛋白表达水平明显降低(P<0.05);与模型组相比,QXJYG干预后,ox-LDL含量、LOX-1、p-P65、VCAM-1、ICAM-1蛋白表达水平显著降低(P<0.05),PPARγ、RXRα表达显著升高(P<0.05)。结论QXJYG显著改善AS大鼠脂代谢紊乱,扩大腹主动脉血管内径,减小腹主动脉血管壁厚度,抑制腹主动脉血管病理损伤,调节血管收缩和舒张功能。QXJYG发挥抗AS的作用机制可能是抑制血脂中ox-LDL水平,降低LOX-1的表达,激活PPARγ、RXRα蛋白,抑制P65的磷酸化,从而降低VCAM-1、ICAM-1蛋白表达。
Objective To elucidate the therapeutic mechanism of Qingxin Jieyu Granule(QXJYG)against atherosclerosis(AS)based on network pharmacology.Methods The major targets and pathways of QXJYG against AS were analyzed using network pharmacology.Rat models of AS established by high-fat feeding combined with intraperitoneal vitamin D3 injection were treated daily with normal saline,atorvastatin(13.15 mg/kg),or QXJYG at 0.99,1.98,and 3.96 g/kg for 8 weeks(n=6).Ultrasound and HE staining were used to assess the function and pathologies of the abdominal aorta.Blood lipids and serum levels of Ang II,ET-1,TXA2,PGI2,and ox-LDL of the rats were detected using an automatic biochemical analyzer or ELISA.The expressions of LOX-1,PPARγ,RXRα,p-P65,VCAM-1 and ICAM-1 in the abdominal aorta were detected with immunohistochemistry.Results The rat models of AS showed obvious abdominal aorta wall thickening,increased pulse wave velocity and pulse index,decreased inner diameter of the abdominal aorta,elevated levels of TC,LDL-C,Ang II,ET-1 and TXA2,and lowered levels of HDL-C and PGI2.QXJYG and atorvastatin treatment of the rat models significantly alleviated histopathological changes of the abdominal aorta,decreased serum levels of TC,LDL-C,Ang II,ET-1 and TXA2,and increased the levels of HDL-C and PGI2.Network pharmacology study suggested the therapeutic effect of QXJYG against AS was mediated by regulating lipid metabolism,PPAR and NF‑κB pathways.Consistently,treatments with QXJYG were found to significantly decrease ox-LDL level and LOX-1,P-P65,VCAM-1 and ICAM-1 protein expressions while increasing PPARγand RXRαexpressions in the aorta of AS rats.Conclusion QXJYG alleviates lipid metabolism disorder and improves histopathological changes of the abdominal aorta of AS rats possibly by lowering ox-LDL level,reducing LOX-1 expression,activating PPARγand RXRα,and inhibiting P65 phosphorylation to reduce VCAM-1 and ICAM-1 expression in the aorta.
作者
张珊苑
蔡巧燕
祁江晗
殷恺馨
何晨晨
高铸烨
张铃
褚剑锋
ZHANG Shanyuan;CAI Qiaoyan;QI Jianghan;YIN Kaixin;HE Chenchen;GAO Zhuye;ZHANG Ling;CHU Jianfeng(College of Integrative Medicine//Academy of Integrative Medicine,Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China;Chen Keji Academic Thought Inheritance Studio,Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China;College of Rehabilitation Medicine,Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China;Fujian Provincial Key Laboratory of Integrative Medicine on Geriatrics,Fuzhou 350122,China;Xiyuan Hospital,China Academy of Chinese Medical Sciences,Beijing 100091,China)
出处
《南方医科大学学报》
CAS
CSCD
北大核心
2024年第8期1518-1528,共11页
Journal of Southern Medical University
基金
福建省科学技术厅中央引导地方科技发展专项(2021L3014)。
