| 引用本文: |
陈洁, 尹凯敏, 何玲, 袁国强.通心络胶囊通过GRP78/XBP1/CHOP途径调控内质网应激减轻大鼠心肌缺血再灌注损伤的作用研究[J].湖南中医药大学学报,2026,46(3):454-463[点击复制] |
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| 通心络胶囊通过GRP78/XBP1/CHOP途径调控内质网应激减轻大鼠心肌缺血再灌注损伤的作用研究 |
| 陈洁,尹凯敏,何玲,袁国强 |
| (河北以岭医院心血管病科, 河北 石家庄 050091) |
| 摘要: |
| 目的 基于葡萄糖调节蛋白78（GRP78）/X盒结合蛋白1（XBP1）/C/EBP同源蛋白（CHOP）途径，探究通心络胶囊（TXL）通过调控内质网应激（ERS）减轻大鼠心肌缺血再灌注损伤（MI/RI）的作用机制。方法 将48只雄性SD大鼠随机均分为6组：假手术（Sham）组、MI/RI组、阳性对照组[MI/RI+阿托伐他汀（ATV），7.2 mg/kg）]、ERS抑制剂组[MI/RI+4-苯基丁酸（4-PBA），500 mg/kg]、TXL组（MI/RI+TXL，1 g/kg）、靶向GRP78抑制剂组（MI/RI+TXL，1 g/kg+HA15，15 mg/kg）。各组大鼠于造模前连续灌胃给药7 d，末次给药后1 h造模。采用左前降支冠状动脉结扎法建立MI/RI模型（缺血50 min，再灌注4 h）。再灌注后，采用超声心动图检测左室射血分数（LVEF）和左心室缩短分数（LVFS）；采用全自动生化分析仪配合相应试剂盒检测血清心肌酶谱[天冬氨酸转氨酶（AST）、乳酸脱氢酶（LDH）、肌酸激酶（CK）、肌酸激酶心肌带（CK-MB）]；采用ELISA检测血清炎症因子[白细胞介素（IL）-1β、IL-18]；采用比色法检测血清氧化应激指标[谷胱甘肽（GSH）、丙二醛（MDA）、总超氧化物歧化酶（T-SOD）]；采用HE染色观察心肌组织病理改变；采用Masson染色检测心肌胶原沉积，计算胶原体积分数（CVF）；采用透射电镜观察内质网超微结构；采用免疫组织化学染色检测胶原蛋白Ⅰ、Ⅲ表达；采用Western blot检测GRP78/XBP1/CHOP通路蛋白表达。结果 与Sham组比较，MI/RI组LVEF、LVFS降低（P<0.01）；血清AST、LDH、CK、CK-MB、IL-1β、IL-18、MDA升高（P<0.01），T-SOD、GSH降低（P<0.01）；心肌纤维排列紊乱伴大量炎症细胞浸润；CVF及胶原蛋白Ⅰ、Ⅲ表达升高（P<0.01）；内质网扩张、肿胀；GRP78、CHOP蛋白表达升高（P<0.01），XBP1蛋白表达降低（P<0.01）。与MI/RI组比较，MI/RI+ATV组、MI/RI+4-PBA组、MI/RI+TXL组、MI/RI+TXL+HA15组LVEF、LVFS升高（P<0.01）；血清AST、LDH、CK、CK-MB、IL-1β、IL-18、MDA降低（P<0.01），T-SOD、GSH升高（P<0.01）；心肌纤维排列紊乱和炎症浸润均改善；CVF及胶原蛋白Ⅰ、Ⅲ表达降低（P<0.01）；内质网超微结构损伤减轻；GRP78、CHOP蛋白表达降低（P<0.01），XBP1蛋白表达升高（P<0.01）。与MI/RI+TXL组比较，MI/RI+TXL+HA15组LVEF、LVFS升高（P<0.01）；血清AST、LDH、CK、CK-MB、IL-1β、IL-18、MDA降低（P<0.05），T-SOD、GSH升高（P<0.05）；CVF及胶原蛋白Ⅰ、Ⅲ表达降低（P<0.05）；GRP78、CHOP蛋白表达降低（P<0.05），XBP1蛋白表达升高（P<0.05）。结论 TXL可通过调控ERS减轻大鼠MI/RI，且可能与GRP78/XBP1/CHOP途径有关。 |
| 关键词: 心肌缺血再灌注损伤 通心络胶囊 葡萄糖调节蛋白78 X盒结合蛋白1 C/EBP同源蛋白 内质网应激 |
| DOI：10.3969/j.issn.1674-070X.2026.03.004 |
| 投稿时间：2025-10-29 |
| 基金项目:河北省医学科学研究课题计划（20251537）。 |
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| Effects of Tongxinluo Capsule on myocardial ischemia-reperfusion injury in rats by modulating ERS through the GRP78/XBP1/CHOP pathway |
| CHEN Jie, YIN Kaimin, HE Ling, YUAN Guoqiang |
| (Department of Cardiovascular Diseases, Hebei Yiling Hospital, Shijiazhuang, Hebei 050091, China) |
| Abstract: |
| Objective To investigate the mechanism of action of Tongxinluo Capsule (TXL) in alleviating myocardial ischemia-reperfusion injury (MI/RI) in rats by regulating endoplasmic reticulum stress (ERS) via the glucose-regulated protein 78 (GRP78)/X-box binding protein 1 (XBP1)/C/EBP homologous protein (CHOP) pathway. Methods Forty-eight male SD rats were randomly divided into six groups: Sham operation (Sham) group, MI/RI group, positive control group [MI/RI+Atorvastatin (ATV), 7.2 mg/kg], ERS inhibitor group [MI/RI+4-phenylbutyric acid (4-PBA), 500 mg/kg], TXL group (MI/RI+TXL, 1 g/kg), and targeted GRP78 inhibitor group (MI/RI+TXL, 1 g/kg+HA15, 15 mg/kg). Rats in each group received continuous intragastric administration for 7 days before modeling, with modeling performed 1 hour after the last dose. The MI/RI model was established by left anterior descending coronary artery ligation (50 minutes of ischemia followed by 4 hours of reperfusion). After reperfusion, left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were measured using echocardiography. Serum myocardial enzyme profiles [aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), and creatine kinase myocardial band (CK-MB)] were tested using an automatic biochemical analyzer with corresponding kits. Serum inflammatory cytokines [interleukin (IL)-1β and IL-18] were measured by ELISA. Serum oxidative stress indicators [glutathione (GSH), malondialdehyde (MDA), and total superoxide dismutase (T-SOD)] were determined using colorimetric assays. Myocardial tissue pathological changes were observed by HE staining. Myocardial collagen deposition was tested by Masson staining, and the collagen volume fraction (CVF) was calculated. Endoplasmic reticulum ultrastructure was observed by transmission electron microscopy. Collagen types Ⅰ and Ⅲ expressions were determined by immunohistochemical staining. GRP78/XBP1/CHOP pathway protein expression was measured by Western blot. Results Compared with the Sham group, the MI/RI group showed decreased LVEF and LVFS (P<0.01); increased serum AST, LDH, CK, CK-MB, IL-1β, IL-18, and MDA (P<0.01); decreased T-SOD and GSH (P<0.01); disordered myocardial fibers with extensive inflammatory cell infiltration; increased CVF and collagen Ⅰ/Ⅲ expressions (P<0.01); dilated and swollen endoplasmic reticulum; increased protein expressions of GRP78 and CHOP (P<0.01); and decreased protein expression of XBP1 (P<0.01). Compared with the MI/RI group, the MI/RI+ATV group, MI/RI+4-PBA group, and MI/RI+TXL group showed increased LVEF and LVFS (P<0.01); decreased serum AST, LDH, CK, CK-MB, IL-1β, IL-18, and MDA (P<0.01); increased T-SOD and GSH (P<0.01); improved myocardial fiber arrangement disorder and inflammatory infiltration; decreased CVF and collagen Ⅰ/Ⅲ expressions (P<0.01); alleviated endoplasmic reticulum ultrastructural damage; decreased protein expressions of GRP78 and CHOP (P<0.01); and increased XBP1 protein expression (P<0.01). Compared with the MI/RI+TXL group, the MI/RI+TXL+HA15 group showed increased LVEF and LVFS (P<0.01); decreased serum AST, LDH, CK, CK-MB, IL-1β, IL-18, and MDA (P<0.05); increased T-SOD and GSH (P<0.05); decreased CVF and collagen Ⅰ/Ⅲ expressions (P<0.05); decreased protein expressions of GRP78 and CHOP (P<0.05); and increased XBP1 protein expression (P<0.05). Conclusion TXL can alleviate MI/RI in rats by regulating ERS, and this effect may be related to the GRP78/XBP1/CHOP pathway. |
| Key words: myocardial ischemia-reperfusion injury Tongxinluo Capsule glucose-regulating protein 78 X-box-binding protein 1 C/EBP homologous protein endoplasmic reticulum stress |
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