丹参酮ⅡA抗ApoE^(-/-)小鼠冠心病伴抑郁的作用及机制研究

Study on the Mechanism of TanshinoneⅡA against Coronary Heart Disease with Comorbid Depression in ApoE^(-/-) Mice

目的研究丹参酮ⅡA对ApoE^(-/-)小鼠冠心病伴抑郁的影响及作用机制。方法采用高脂饲料喂养ApoE^(-/-)小鼠,并进行慢性不可预知温和应急(CUMS)构建冠心病伴抑郁小鼠模型。将小鼠随机分为正常组、模型组、丹参酮ⅡA低剂量组(30 mg·kg^(-1))和丹参酮ⅡA高剂量组(60 mg·kg^(-1))。采用HE和油红O染色检测ApoE^(-/-)小鼠心脏主动脉窦的病理变化;强迫游泳实验(FST)、悬尾实验(TST)和糖水偏好实验(SPT)观察ApoE^(-/-)小鼠抑郁样行为;ELISA法检测小鼠血脂及炎症因子水平;Western blot检测心脏主动脉窦组织和海马组织的炎症相关蛋白表达水平。结果与正常组相比,模型组ApoE^(-/-)小鼠心脏主动脉内膜脂质积累显著增加,血脂及促炎因子显著升高(P<0.01),FST和TST不动时间显著增加(P<0.01),SPT蔗糖偏好率显著降低(P<0.01),心脏主动脉窦组织和海马组织中p-GSK3β(Ser9)/GSK3β、p-CREB(Ser133)/CREB和p-NF-κB/NF-κB的比值显著增加(P<0.01)。与模型组相比,丹参酮ⅡA高、低剂量组ApoE^(-/-)小鼠心脏主动脉内膜脂质积累显著减少,血脂及促炎因子水平显著降低(P<0.01),FST和TST不动时间显著减少(P<0.01),SPT蔗糖偏好率显著增加(P<0.01)。p-GSK3β(Ser9)/GSK3β和p-CREB(Ser133)/CREB的比值进一步呈剂量依赖性增加(P<0.05,P<0.01),p-NF-κB/NF-κB比值呈剂量依赖性降低(P<0.01)。结论丹参酮ⅡA具有显著的抗ApoE^(-/-)小鼠冠心病伴抑郁作用,其机制可能是通过调节GSK3β的表达,继而影响NF-κB与CREB的活化来实现的。

OBJECTIVE To investigate the effect and mechanism of tanshinoneⅡA against coronary heart disease with comorbid depression in ApoE^(-/-) mice.METHODS The model of coronary heart disease with comorbid depression was established by feeding high fat diet and carrying out chronic unpredictable mild stress(CUMS).Mice were randomly divided into normal group,model group,tanshinoneⅡA low dose group(30 mg·kg^(-1))and tanshinoneⅡA high dose group(60 mg·kg^(-1)).Hematoxylin-eosin(HE)and oil red O staining were used to detect the pathological changes of cardiac aortic sinus in ApoE^(-/-) mice.Forced swimming test(FST),tail suspension test(TST)and sucrose preference test(SPT)were used to observe the depression-like behaviors of ApoE^(-/-) mice.The levels of blood lipid and inflammatory factors were detected by ELISA assay.The expressions of inflammation related proteins in cardiac aortic sinus and hippocampus were detected by Western blot.RESULTS Compared with the normal group,the lipid accumulation in the cardiac aortic intima in the model group increased significantly,the levels of blood lipid and pro-inflammatory factors increased significantly(P<0.01),the immobility time of FST and TST significantly increased(P<0.01),while the sucrose preference rate of SPT significantly decreased(P<0.01),the ratios of p-GSK3β(Ser9)/GSK3β,p-NF-κB/NF-κB and p-CREB(Ser133)/CREB in cardiac aortic sinus and hippocampus increased significantly(P<0.01).Compared with the model group,the treatment with tanshinoneⅡA significantly reduced the accumulation of lipid in cardiac aortic intima,the levels of blood lipid and pro-inflammatory factors and the immobility time of FST and TST decreased significantly(P<0.01),the sucrose preference rate of SPT significantly increased(P<0.01),the ratio of p-NF-κB/NF-κB decreased significantly(P<0.01),and the ratios of p-GSK3β(Ser9)/GSK3βand p-CREB(Ser133)/CREB increased significantly(P<0.05,P<0.01).CONCLUSION TanshinoneⅡA has a significant effect against coronary heart disease with comorbid depression in ApoE^(-/-) mice,and its mechanism may be related to the regulation of GSK3β,and further activation of NF-κB and CREB.