基于IL-6/STAT3/GPX4通路探讨瑞芬太尼对扩张型心肌病大鼠心肌纤维化的影响OA
Effect of remifentanil on myocardial fibrosis in rats with dilated cardiomyopathy through interleukin-6/signal transducer and activator of transcription 3/glutathione peroxidase 4 pathway
目的 通过白细胞介素-6(IL-6)/信号转导与转录激活因子 3(STAT3)/谷胱甘肽过氧化物酶4(GPX4)通路探讨瑞芬太尼(Rem)对扩张型心肌病(DCM)大鼠心肌纤维化的作用机制.方法 于大鼠腹腔注射 2.5 mg/kg阿霉素构建DCM大鼠模型,将其分为模型(Model)组、Rem低剂量(Rem-L,2 μg/kg)组、Rem中剂量(Rem-M,4 μg/kg)组、Rem高剂量(Rem-H,8 μg/kg)组、Rem高剂量+Colivelin(STAT3 激活剂)(Rem-H+Colivelin,8 μg/kg Rem+1 mg/kg Colivelin)组,每组12 只.另设12 只正常Wistar大鼠为对照组(Control).连续给药 4 周后,西门子超声仪检测大鼠左室收缩期末径(LVESD)、左室射血分数(LVEF)、左室舒张期末径(LVEDD)、左室短轴缩短率(LVFS);免疫组化法检测大鼠心肌组织Ⅰ型胶原蛋白(Col Ⅰ)、转化生长因子-β1(TGF-β1)、Ⅲ型胶原蛋白(Col Ⅲ)表达;Masson染色、苏木精-伊红(HE)检测大鼠心肌组织病理变化;Western blot检测IL-6/STAT3/GPX4 通路相关蛋白表达.结果 与Control 组相比,Model 组大鼠心肌组织LVEDD、LVESD、ColⅠ((123.62±10.78)vs(76.53±6.12))、ColⅢ、TGF-β1、IL-6、p-STAT3Tyr705/STAT3((0.95±0.05)vs(0.46±0.02))显著升高,LVEF((52.19±4.88)%vs(76.78±6.97)%)、LVFS、溶质载体家族 7 成员11(SLC7A11)、GPX4((0.11±0.01)vs(0.43±0.04))显著降低(P＜0.05),出现炎性浸润、胶原蛋白堆积和心肌纤维化现象;与Model组相比,Rem-M、Rem-H组大鼠心肌组织中LVEDD、LVESD、Col Ⅰ((98.74±7.28)、(84.27±7.13)vs(123.62±10.78))、ColⅢ、TGF-β1、IL-6、p-STAT3Tyr705/STAT3((0.81±0.06)、(0.57±0.04)vs(0.95±0.05))显著降低,LVEF((69.85±6.13)%、(72.83±6.55)%vs(52.19±4.88)%)、LVFS、SLC7A11、GPX4((0.24±0.02)、(0.36±0.02)vs(0.11±0.01))显著升高(P＜0.05),心肌炎性损伤和纤维化有所改善;Colivelin可逆转Rem对DCM大鼠心肌纤维化的改善作用.结论 Rem可能通过调控IL-6/STAT3/GPX4 通路,减少胶原蛋白堆积,改善DCM大鼠心肌纤维化及心功能.
Objective To investigate the mechanism of remifentanil(Rem)on myocardial fibrosis in rats with dilated cardiomyopathy(DCM)in relation to the interleukin-6(IL-6)/signal transducer and activator of transcription 3(STAT3)/glutathione peroxidase 4(GPX4)pathway.Methods A DCM rat model was established by intraperitoneal injection of 2.5 mg/kg doxorubicin.The rats were then divided into Model,low-dose(Rem-L,2 μg/kg),medium-dose(Rem-M,4 μg/kg),and high-dose Rem groups(Rem-H,8 μg/kg),and a high-dose Rem+Colivelin(STAT3 activator,Rem-H+Colivelin,8 μg/kg Rem+1 mg/kg Colivelin)group(n=12 rats per group).Another 12 normal Wistar rats were set as a Control group.After continuous administration for 4 weeks,left ventricular end systolic diameter(LVESD),left ventricular ejection fraction(LVEF),left ventricular end diastolic diameter(LVEDD),and left ventricular fractional shortening(LVFS)were measured by ultrasound.Type Ⅰcollagen(Col Ⅰ),transforming growth factor-β1(TGF-β1),and type Ⅲ collagen(Col Ⅲ)expression in myocardial tissue were detected by immunohistochemistry.Pathological changes in myocardial tissue were detected by Masson and hematoxylin/eosin staining.IL-6/STAT3/GPX4 pathway-related proteins were detected by Western blot.Results Compared with the Control group,rats in the Model group showed obvious increases in LVEDD,LVESD,ColⅠ((123.62±10.78)vs(76.53±6.12)),ColⅢ,TGF-β1,IL-6,and phospho-STAT3Tyr705/STAT3((0.95±0.05)vs(0.46±0.92))in myocardial tissue,and decreases in LVEF((52.19±4.88)%vs(76.78±6.97)%),LVFS,SLC7A11,and GPX4((0.11±0.01)vs(0.43±0.04))(P＜0.05),inflammatory infiltration,collagen accumulation,and myocardial fibrosis.Compared with the Model group,rats in the Rem-M and Rem-H groups showed reduced LVEDD,LVESD,ColⅠ((98.74±7.28)、(84.27±7.13)vs(123.62±10.78)),ColⅢ,TGF-β1,IL-6,and p-STAT3Tyr705/STAT3((0.81±0.06)、(0.57±0.04)vs(0.95±0.05))in myocardial tissue,increases in LVEF((69.85±6.13)%、(72.83±6.55)%vs(52.19±4.88)%),LVFS,SLC7A11,and GPX4((0.24±0.02)、(0.36±0.02)vs(0.11±0.01))(P＜0.05),and improvements in myocarditis injury and fibrosis.Colivelin was able to reverse the improving effect of Rem on myocardial fibrosis in DCM rats.Conclusions Rem may reduce collagen accumulation and improve myocardial fibrosis and cardiac function in DCM rats by adjusting the IL-6/STAT3/GPX4 pathway.
周芳;刘杨;邓佳
四川省医学科学院·四川省人民医院麻醉科,成都 610000四川省医学科学院·四川省人民医院麻醉科,成都 610000四川省医学科学院·四川省人民医院麻醉科,成都 610000
医药卫生
瑞芬太尼扩张型心肌病纤维化IL-6/STAT3/GPX4通路
remifentanildilated cardiomyopathyfibrosisIL-6/STAT3/GPX4 pathway
《中国比较医学杂志》 2026 (6)
21-30,10
四川省卫生健康委员会科技项目(24QNMP097).
评论