GV1001抑制cGAS/STING通路缓解阿霉素诱导的小鼠心脏毒性

GV1001 alleviates doxorubicin-induced cardiotoxicity by inhibiting cGAS/STING signaling pathway

目的:探讨端粒酶衍生肽GV1001对阿霉素(DOX)诱导的小鼠心脏毒性的保护作用及其潜在机制。方法:使用C57BL/6小鼠建立DOX心脏毒性动物模型,分为对照组、DOX组(20 mg/kg)与不同剂量GV1001(6、30和60μmol/kg)组。检测各组小鼠心功能,取血清行心肌损伤标志物检测;取心脏组织进行HE染色及Masson染色;采用分光光度法测定心肌MDA、T-SOD和GSH-PX水平;提取心脏组织蛋白,Western blot法检测环状GMP-AMP合成酶(cGAS)、磷酸化干扰素基因刺激因子(STING)和干扰素调节因子3(IRF3)蛋白的表达水平。并使用STING激动剂后检测心肌组织损伤和氧化应激的改变。结果:与对照组比,DOX组小鼠LVIDd、LVEF和LVFS降低,LVIDs值增加,心肌纤维排列紊乱,细胞核固缩、空泡化,胶原沉积增加(均P<0.05);同时血清心肌酶学指标cTnI、CK-MB和LDH升高,心肌组织MDA增加,而T-SOD和GSH-PX下降(均P<0.05)。与DOX组对比,不同剂量GV1001组小鼠LVIDd、LVEF和LVFS升高,心肌损伤减轻,空泡化减轻,胶原沉积下降,血清cTnI、CK-MB和LDH下降,心肌组织MDA下降,T-SOD和GSH-PX升高(均P<0.05)。与对照组比较,DOX组小鼠心脏组织中cGAS、p-STING和p-IRF3的蛋白表达量均升高(P<0.05);DOX小鼠经GV1001治疗后cGAS、p-STING和p-IRF3的表达下降(P<0.05)。使用STING激动剂agonist干预后,GV1001对DOX小鼠心功能的改善作用减弱,对心脏组织氧化应激的抑制减轻。结论:GV1001可以缓解DOX诱导的小鼠心肌损伤,其机制可能是通过抑制cGAS/STING通路减轻氧化应激水平。

Objective:To investigate the protective effect of telomerase-derived peptide GV1001 on doxorubicin(DOX)-induced cardiac toxicity in mice and its potential mechanisms.Methods:A DOX-induced cardiac toxicity animal model was established in C57BL/6 mice by administering DOX(20 mg/kg),which were divided as the control group,DOX group,GV1001 groups of different concentration(6,30 and 60μmol/kg).Mouse’s cardiac function was assessed,and markers of myocardial injury were detected in serum;heart tissues were subjected to HE staining and Masson staining;myocardial levels of MDA,T-SOD,and GSH-PX were measured using spectrophotometry;protein was extracted from heart tissue,and Western blot was performed to evaluate the expression levels of cyclic GMP-AMP synthase(cGAS),phosphorylated stimulator of interferon genes(STING),and IRF3.Changes in myocardial tissue damage and oxidative stress were also assessed after administration of STING agonist.Results:Compared with the control group,mice in the DOX group exhibited decreased LVIDd,LVEF,and LVFS,increased LVIDs,disrupted myocardial fiber arrangement,nuclear condensation,vacuolization,and increased collagen deposition(all P<0.05).Concurrently,serum myocardial enzyme cTnI,CK-MB and LDH were increased,and so did myocardial MDA levels,while SOD and GSH levels decreased(all P<0.05).Compared with the DOX group,mice in the GV1001 groups of different dose showed increased LVIDd,LVEF,and LVFS,reduced myocardial damage,mitigatory vacuolization,decreased collagen deposition,lower serum levels of cTnI,CK-MB and LDH,lower myocardial MDA level and increased T-SOD and GSH-PX levels(all P<0.05).Compared with the control group,the expressions of cGAS,p-STING,and p-IRF3 protein in the hearts of DOX-treated mice were all increased(P<0.05).After treatment with GV1001,the expressions of cGAS,p-STING,and p-IRF3 were decreased(P<0.05)in DOX-treated mice.The improvement of cardiac function by GV1001 in DOX-treated mice was attenuated,and the inhibition of oxidative stress in cardiac tissue was reduced after administration with STING agonist.Conclusion:GV1001 can alleviate DOX-induced myocardial damage in mice,possibly by reducing oxidative stress levels through the inhibition of the cGAS/STING pathway.