摘要
目的探讨胸痞方通过干预Janus激酶2/转录激活因子3(JAK2/STAT3)通路及糖皮质激素受体治疗冠心病合并抑郁症的机制。方法将雄性SD大鼠随机分为正常组,模型组,阳性对照组,胸痞方高、中、低剂量治疗组6组。除正常组外,对其余大鼠进行慢性不可预知刺激+皮下注射异丙肾上腺素(CUMS+ISO)诱导冠心病合并抑郁症模型。造模成功后治疗组均灌服不同剂量的胸痞方水煎液(高、中、低剂量分别含生药32.97、16.49、8.24 g/kg);阳性对照组灌胃酒石酸美托洛尔2.13 mg/kg+舍曲林5.25 mg/kg;模型组、正常组灌胃等体积生理盐水溶液。造模前后检测大鼠心电图,并记录大鼠强迫游泳时间、旷场实验评分。ELISA法测定大鼠血清皮质醇(cortisol,CORT)含量,Western blot、RT-PCR法测定大鼠心肌及前额叶皮层中JAK2、p-JAK2、STAT3、p-STAT3蛋白含量以及前额叶皮层糖皮质激素受体(glucocorticoid receptors,GR)、盐皮质激素受体(mineralocorticoid receptors,MR)mRNA表达水平。结果心电图结果显示,经CUMS+ISO诱导后各造模组大鼠心电图ST段高度较正常组均显著升高(P<0.01)。灌胃3周后,除胸痞方低剂量组外,各给药组ST段高度较模型组均显著降低(P<0.01)。阳性对照组以及胸痞方中、高剂量组ST段位移显著高于模型组(P<0.05),但各给药组间比较差异无统计学意义(P>0.05)。行为学实验显示,造模完成后,各组大鼠旷场实验水平运动及垂直运动较正常组均显著下降(P<0.01或P<0.05)。灌药3周后,阳性对照组以及胸痞方低、中、高剂量组大鼠水平运动距离较模型组均显著升高(P<0.01)。阳性对照组、胸痞方中剂量组大鼠垂直运动距离较模型组显著升高(P<0.05),但两组间比较差异无统计学意义(P>0.05)。与正常大鼠比较,模型大鼠血清CORT含量,前额叶皮层MR mRNA表达,心肌JAK2、p-JAK2、STAT3、p-STAT3蛋白表达,以及前额叶皮层p-JAK2、p-STAT3蛋白表达均显著升高(P<0.01或P<0.05),前额叶皮层GR mRNA表达显著降低(P<0.01)。与模型组比较,药物灌胃3周后阳性对照组、胸痞方治疗组大鼠血清CORT含量均显著降低(P<0.05或P<0.01),其中胸痞方高、中剂量组效果显著优于阳性对照组(P<0.01或P<0.05)。与模型组比较,胸痞方高、中、低剂量组及阳性对照组心肌p-JAK2、p-STAT3蛋白表达均有不同程度降低(P<0.05或P<0.01)。与模型组比较,胸痞方低、中、高剂量组及阳性对照组前额叶皮层p-STAT3蛋白表达均显著降低(P<0.01),胸痞方高剂量组及中剂量组p-JAK2蛋白表达均降低(P<0.01或P<0.05)。与模型组比较,胸痞方高、中、低剂量组及阳性对照组GR mRNA表达显著升高(P<0.01);胸痞方高剂量组及阳性对照组前额叶皮层组织MR mRNA表达降低(P<0.05或P<0.01)。结论胸痞方能够显著改善冠心病合并抑郁大鼠的抑郁样行为及心肌缺血情况,其作用机制可能与维持下丘脑-垂体-肾上腺轴(HPA轴)稳态以及调节JAK2/STAT3信号通路有关。
Objective To investigate the mechanism of Xiongpi Decoction(胸痞方)in the treatment of coronary heart disease(CHD)complicated with depression by interfering JAK2/STAT3 pathway and glucocorticoid receptor.Methods Male SD rats were randomly divided into 6 groups:normal group(N),model group(M),control group(C),Xiongpi Decoction high-dose(XPF-H),medium-dose(XPF-M)and low-dose(XPF-L)groups.Except the normal group,the other rats were treated with chronic unpredictable mild stress(CUMS)+subcutaneous injection of isoproterenol(ISO)to induce CHD combined with depression model.After successful modeling,the treatment group was given different doses of Xiongpi Decoction(high,medium and low doses contained crude drug 32.97,16.49 and 8.24 g/kg,respectively).Control group was given Metoprolol tartrate 2.13 mg/kg+Sertraline 5.25 mg/kg intragastric administration.The model group and normal group were given equal volume of normal saline solution intragastric administration.Electrocardiogram was detected before and after modeling,and open field score were recorded.Serum CORT content was determined by ELISA,and the contents of JAK2,p-JAK2,STAT3,p-STAT3 in myocardial and prefrontal cortex of rats were determined by Western blot and RTPCR,as well as the mRNA expression levels of glucocorticoid receptor(GR)and mineralocorticoid receptor(MR)in prefrontal cortex of rats.Results ECG results showed that ST-segment height of ECG of rats in each group was significantly higher than that of normal group after induction of CUMS+ISO(P<0.01).After 3 weeks of ig,ST-segment height in all administration groups was significantly lower than that in model group except low dose group(P<0.01).The ST-segment displacement of positive control group,medium and high dose groups was significantly higher than that of model group(P<0.05),but there was no significant difference among all treatment groups(P>0.05).Behavior experiment showed that after modeling,the horizontal and vertical movement in open field experiment were significantly decreased(P<0.01 or P<0.05).After 3 weeks of administration,the horizontal movement distance of rats in positive control group,low,medium and high treatment groups was significantly higher than that in model group(P<0.01).The vertical movement distance of rats in positive control group and medium dose group was significantly higher than that in model group(P<0.05),but there was no significant difference between the two groups(P>0.05).The expression levels of serum CORT,MR mRNA in prefrontal cortex,JAK2,p-JAK2,STAT3,p-STAT3 in myocardial,and the expression levels of p-JAK2 and p-STAT3 in prefrontal cortex were significantly increased(P<0.05 or P<0.01),while the expression of GR mRNA in prefrontal cortex was significantly decreased(P<0.01).After 3 weeks of intragastric administration of Xiongpi Decoction,the serum CORT content in control group and XPF groups was significantly decreased(P<0.05 or P<0.01),and the effect in XPF-H and XPF-M groups was significantly better than that in control group(P<0.01 or P<0.05).The expression of p-JAK2 and p-STAT3 in myocardium of XPF groups and control group were decreased to varying degrees(P<0.05 or P<0.01).p-STAT3 in prefrontal cortex of XPF groups and control group was significantly decreased(P<0.01),and the expression of p-JAK2 in XPF-H and XPF-M groups was decreased,with statistical significance(P<0.01 or P<0.05).The expression of GR mRNA in XPF groups and control group was significantly increased(P<0.01).MR mRNA expression in prefrontal cortex of XPF-H group and control group was decreased(P<0.05 or P<0.01).Conclusion Xiongpi Decoction can significantly improve depression-like behavior and myocardial ischemia in CHD rats with depression,and its mechanism may be related to maintaining HPA axis homeostasis and regulating JAK2/STAT3 signaling pathway.
作者
邓芳隽
李晓凤
杜武勋
张少强
丛紫东
DENG Fangjuan;LI Xiaofeng;DU Wuxun;ZHANG Shaoqiang;CONG Zidong(Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China;The Second Affiliated Hospital of Tianjin University of Chinese Medicine,Tianjin 300150,China)
出处
《辽宁中医药大学学报》
CAS
2022年第7期26-33,共8页
Journal of Liaoning University of Traditional Chinese Medicine
基金
天津市教委基金(2018KJ014)
天津市科委基金(2019SK025)。
关键词
冠心病
抑郁
胸痞方
JAK/STAT
双心疾病
coronary heart disease
depression
Xiongpi Decoction(胸痞方)
JAK/STAT
psychocardiology disease
