蓝萼甲素调节Akt/Nrf2/HO-1信号通路对冠心病大鼠的影响

Influence of Glaucocalyxin A in rats with coronary heart disease by regulating Akt/Nrf 2/HO-1 signaling pathway

目的:探讨蓝萼甲素(GLA)调节蛋白激酶B(Akt)/核因子E2相关因子2(Nrf2)/血红素氧合酶-1(HO-1)信号通路对冠心病(CHD)大鼠的影响。方法:通过高脂饲料喂养及腹腔注射垂体后叶素制备CHD大鼠模型,设置分组为CHD组、GLA低剂量(GLA-L,5 mg/kg)组、GLA中剂量(GLA-M,10 mg/kg)组、GLA高剂量(GLA-H,20 mg/kg)组、GLA-H+LY294002(Akt/Nrf2/HO-1通路抑制剂,20 mg/kg GLA-H+40 mg/kg LY294002)组,同时以基础饲料喂养及腹腔注射生理盐水的10只大鼠为对照组;干预结束后,分别检测各组大鼠血清中血脂代谢水平[低密度脂蛋白胆固醇(LDL-C)、总胆固醇(TC)以及三酰甘油(TG)]、血管内皮功能指标[内皮素-1(ET-1)、一氧化氮(NO)]、炎症因子水平(IL-6、TNF-α)、心脏组织中氧化应激水平[丙二醛(MDA)、总抗氧化能力(T-AOC)]以及病理学及斑块面积变化、Akt/Nrf2/HO-1通路相关蛋白表达水平。结果:与对照组相比,CHD组NO、T-AOC含量、PI3K、p-Akt/Akt、Nrf2、HO-1表达显著降低,ET-1、MDA、TNF-α、IL-6、TG、TC、LDL-C含量显著增加(P<0.05);与CHD组相比,GLA-L组、GLA-M组、GLA-H组NO、T-AOC含量、PI3K、p-Akt/Akt、Nrf2、HO-1表达显著增加,ET-1、MDA、TNF-α、IL-6、TG、TC、LDL-C含量显著降低(P<0.05);与GLA-H组相比,GLA-H+LY294002组NO、T-AOC含量、PI3K、p-Akt/Akt、Nrf2、HO-1表达显著降低,ET-1、MDA、TNF-α、IL-6、TG、TC、LDL-C含量显著增加(P<0.05)。结论:GLA可以通过激活Akt/Nrf2/HO-1信号通路抑制炎症反应及氧化应激水平,改善CHD大鼠病理损伤及内皮功能障碍。

Objective:To investigate the influence of Glaucocalyxin A(GLA)in rats with coronary heart disease(CHD)by regulating protein kinase B(Akt)/nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling pathway.Methods:The CHD rat model was prepared by feeding high-fat diet and intraperitoneal injection of pituitary hormone,and grouped into CHD group,GLA low-dose(GLA-L,5 mg/kg)group,GLA medium-dose(GLA-M,10 mg/kg)group,GLA high-dose(GLA-H,20 mg/kg)group,and GLA-H+LY294002(Akt/Nrf2/HO-1 pathway inhibitor,20 mg/kg GLA-H+40 mg/kg LY294002)group,meantime,10 rats fed with basal diet and intraperitoneally injected with normal saline were used as control group;after the intervention,the serum lipid metabolism levels[low-density lipoprotein cholesterol(LDL-C),total cholesterol(TC)and triacylglycerol(TG)],vascular en-dothelial function indexes[endothelin-1(ET-1),nitric oxide(NO)],inflammatory factor levels(IL-6,TNF-α),oxidative stress lev-els in cardiac tissue[malondialdehyde(MDA),total antioxidant capacity(T-AOC)],pathological and plaque area changes,and ex-pression levels of Akt/Nrf2/HO-1 pathway-related proteins were measured.Results:Compared with control group,the contents of NO and T-AOC,and the expressions of PI3K,p-Akt/Akt,Nrf2 and HO-1 in the CHD group were greatly decreased,the contents of ET-1,plaque area,MDA,TNF-α,IL-6,TG,TC and LDL-C were greatly increased(P<0.05);compared with CHD group,the contents of NO and T-AOC,and the expressions of PI3K,p-Akt/Akt,Nrf2 and HO-1 in GLA-L group,GLA-M group,GLA-H group were greatly increased,while the contents of ET-1,plaque area,MDA,TNF-α,IL-6,TG,TC and LDL-C were greatly decreased(P<0.05);compared with GLA-H group,the contents of NO and T-AOC,and the expressions of PI3K,p-Akt/Akt,Nrf2 and HO-1 in the GLA-H+LY294002 group were greatly decreased,the contents of ET-1,plaque area,MDA,TNF-α,IL-6,TG,TC and LDL-C were great-ly increased(P<0.05).Conclusion:GLA can inhibit the inflammatory response and oxidative stress level by activating the Akt/Nrf2/HO-1 signaling pathway,and ameliorate the pathological damage and endothelial dysfunction in CHD rats.