| 244 | 0 | 14 |
| 下载次数 | 被引频次 | 阅读次数 |
目的 基于环磷酸鸟苷-腺苷合成酶(cGAS)-干扰素基因刺激因子(STING)信号通路探讨雪莲注射液对小鼠心肌缺血再灌注损伤(MIRI)的保护作用。方法 选40只SPF级雄性C57BL/6小鼠为研究对象，取10只作为假手术组，仅开胸但不结扎冠状动脉，其余30只制备MIRI模型，造模成功后按随机数字表法分为模型组、雪莲组和RU.521组。雪莲组给予4.11 mg/kg的雪莲注射液腹腔注射，RU.521组给予5 mg/kg的RU.521腹腔注射，假手术组与模型组腹腔注射与雪莲组等体积的0.9%氯化钠注射液。治疗7 d后，采用超声心动图检测左室舒张末期容积(LVEDV)、左室收缩末期容积(LVESV)、左室射血分数(LVEF)、左室短轴缩短率(LVFS),苏木素-伊红(HE)染色观察心肌组织病理形态，末端脱氧核苷酸转移酶介导的缺口末端标记(TUNEL)法测定心肌细胞凋亡指数(AI),比色法测定肌酸激酶(CK)浓度，微板法检测乳酸脱氢酶(LDH)含量，酶联免疫吸附(ELISA)法检测白细胞介素(IL)-6、肿瘤坏死因子(TNF)-α水平，蛋白免疫印迹(WB)法检测cGAS、 STING和B淋巴细胞瘤-2基因(Bcl-2)、 Bcl-2相关X蛋白(Bax)表达。结果 与假手术组比较，模型组CK、LDH、IL-6、TNF-α、cGAS、STING、Bax、Bax/Bcl-2、AI、LVEDV、LVESV均显著升高(P<0.01或P<0.05),Bcl-2、LVEF、LVFS明显降低(P<0.01或P<0.05),且心肌组织间隙增宽、排列紊乱伴炎性细胞浸润。与模型组相比，雪莲组和RU.521组的CK、LDH、IL-6、TNF-α、cGAS、STING、Bax、Bax/Bcl-2、AI、LVEDV、LVESV均显著下降(P<0.01或P<0.05),Bcl-2、LVEF、LVFS明显上升(P<0.01或P<0.05),且心肌组织的病理性损伤亦减轻。结论 雪莲注射液对小鼠MIRI具有保护作用，其机制可能与cGAS-STING信号通路的抑制有关。
Abstract：Objective To observe the protective effect of Xuelian injectionon myocardial ischemia-reperfusion injury(MIRI) in mice based on cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING) signaling pathway. Methods 40 SPF male C57BL/6 mice were selected as study objects, 10 mice were selected as sham group, and only underwent thoracotomy without coronary artery ligation, the remaining 30 mice were successfully established MIRI model and randomly divided into model group, Xuelian group and RU.521 group with 10 mice per group. Xuelian group was injected intraperitoneally with Xuelian injection at a dose of 4.11 mg/kg, RU.521 group was injected intraperitoneally with RU.521 injection at a dose of 5 mg/kg, and the sham group and model group were injected intraperitoneally with 0.9% sodium chloride injection in the same volume as Xuelian group. After 7 days of the treatment, the levels of left ventricular end-diastolic volume(LVEDV), left ventricular end-systolic volume(LVESV), left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS) were measured by using echocardiography. The pathological morphology of myocardial tissue was observed by haematoxylin-eosin(HE) staining. Cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL). Lactate dehydrogenase(LDH) content was measured by microplate method, and creatine kinase(CK) concentration was determined by colorimetric method. Interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) levels were detected by enzyme linked immunosorbent assay(ELISA). The expressions of cGAS, STING, B cell lymphoma(Bcl)-2 and Bcl-2-associated X protein(Bax) were detected by Western blotting. Results Compared with sham group, the concentrations of CK, LDH, IL-6 and TNF-α, the expression of cGAS, STING, Bax and Bax/Bcl-2 ratio, the levels of AI, LVEDV and LVESV were increased significantly(P<0.01 or P<0.05), while the expression of Bcl-2 and the levels of LVEF and LVFS was decreased significantly in the model group(P<0.01 or P<0.05), along with widened interstitium, disordered arrangement and inflammatory cells infiltration in the myocardial tissue. Compared with model group, the concentrations of CK, LDH, IL-6 and TNF-α, the expression of cGAS, STING, Bax and Bax/Bcl-2 ratio, the levels of AI, LVEDV and LVESV was decreased significantly(P<0.01 or P<0.05), while the expression of Bcl-2 and the levels of LVEF and LVFS were increased significantly in Xuelian group and RU.521 group(P<0.01 or P<0.05), and the myocardial histopathological damage was reduced. Conclusion Xuelian injection has a protective effect on MIRI, and the mechanism may be related to the inhibition of cGAS-STING signaling pathway.
[1] 中华医学会心血管病学分会，中华心血管病杂志编辑委员会.急性ST段抬高型心肌梗死诊断和治疗指南(2019)[J].中华心血管病杂志，2019,47(10):766-783.
[2] 阿迪拉·阿布都热西提，仲春红，阿曼古丽·如则，等.雌酮硫酸钠的制备及其对小鼠心肌缺血再灌注损伤保护作用的研究[J].新疆医科大学学报，2024,47(5):734-739.
[3] LUO W,BIAN X,LIU X,et al.A new method for the treatment of myocardial ischemia-reperfusion injury based on γδT cell-mediated immune response[J].Front Cardiovasc Med,2023,10:1219316.
[4] HAO F.An overview of the crosstalk between YAP and cGAS-STING signaling in non-small cell lung cancer:it takes two to tango[J].Clin Transl Oncol,2022,24(9):1661-1672.
[5] XU D,TIAN Y,XIA Q,et al.The cGAS-STING pathway:Novel perspectives in liver diseases[J].Front Immunol,2021,12:682736.
[6] 庞昀婷，孟凡青，石枫.cGAS/STING信号通路在心肌缺血再灌注损伤中的作用[J].国际心血管病杂志，2024,51(4):200-203.
[7] YU H,FU J,GUO H H,et al.Metabolites analysis of anti-myocardial ischemia active components of saussurea involucrata based on gut microbiota-drug interaction[J].Int J Mol Sci,2022,23(13):7457.
[8] 张朋朋，李琳，石志群，等.雪莲黄酮胶囊对高原缺氧诱导小鼠心肌损伤的保护作用研究[J].药学实践杂志，2022,40(5):403-407,432.
[9] VINCENT J,ADURA C,GAO P,et al.Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice[J].Nat Commun,2017,8(1):750.
[10] 臧光耀，李波，耿田欣，等.一种快速建立小鼠心肌缺血再灌注模型的方法[J].江苏大学学报(医学版),2019,29(6):472-475.
[11] NAIR A,MORSY M A,JACOB S.Dose translation between laboratory animals and human in preclinical and clinical phases of drug development[J].Drug Dev Res,2018,79(8):373-382.
[12] 党辉，艾山江，补娟，等.雪莲提取物预处理对局灶性脑缺血再灌注小鼠Toll样受体4和核因子-KB表达的影响[J].国际脑血管病杂志，2012,20(9):690-695.
[13] XU Q,XIONG H,ZHU W,et al.Small molecule inhibition of cyclic GMP-AMP synthase ameliorates sepsis-induced cardiac dysfunction in mice[J].Life Sci,2020,260:118315.
[14] ZHOU M,YU Y,LUO X,et al.Myocardial ischemia-reperfusion injury:Therapeutics from a mitochondria-centric perspective[J].Cardiology,2021,146(6):781-792.
[15] LI J K,SONG Z P,HOU X Z.Scutellarin ameliorates ischemia/reperfusion injuryinduced cardiomyocyte apoptosis and cardiac dysfunction via inhibition of the cGASSTING pathway[J].Exp Ther Med,2023,25(4):155.
[16] KING K R,AGUIRRE A D,YE Y X,et al.IRF3 and type I interferons fuel a fatal response to myocardial infarction[J].Nat Med,2017,23(12):1481-1487.
[17] LAI L,ZHANG A,YANG B,et al.Plasmacytoid dendritic cells mediate myocardial ischemia/reperfusion injury by secreting type Iinterferons[J].J Am Heart Assoc,2021,10(15):e020754.
[18] FAN W X,YANG W P,LIU H S.Research progress on culture technologies,chemical components,and pharmacological activities of saussurea involucrata cells[J].Zhongguo Zhong Yao Za Zhi,2021,46(14):3522-3528.
[19] JAGDEEP K,MAHIMA P.Phytochemistry and pharmacology of saussurea genus (saussurea lappa,saussurea costus,saussurea obvallata,saussurea involucrata)[J].Mater Today:Proc,2022,56(P3):1173-1181.
[20] GONG G,HUANG J,YANG Y,et al.Saussureae involucratae herba (snow lotus):Review of chemical compositions and pharmacological properties[J].Front Pharmacol,2020,10:1549.
[21] SUN B,OU H,REN F,et al.Propofol protects against cerebral ischemia/reperfusion injury by down-regulating long noncoding RNA SNHG14[J].ACS Chem Neurosci,2021,12(16):3002-3014.
[22] MA D,QIAO J,QU Q,et al.Weighted gene co-expression network analysis to investigate the key genes implicated in global brain ischemia/reperfusion injury in rats[J].Adv Clin Exp Med,2020,29(6):649-659.
[23] 阮文婷，魏希进，管琳.可溶性生长刺激表达因子2与急性心肌梗死后左心室重塑的相关性分析[J].医学临床研究，2022,39(1):41-43,47.
[24] LIU M,AI J,FENG J,et al.Effect of paeoniflorin on cardiac remodeling in chronic heart failure rats through the transforming growth factor β1/smad signaling pathway[J].Cardiovasc Diagn Ther,2019,9(3):272-280.
[25] NAWAZ W,NAVEED M,ZHANG J,et al.Cardioprotective effect of silicon-built restraint device (ASD),for left ventricular remodeling in rat heart failure model[J].J Mater Sci Mater Me,2022,33(5):42.
[26] COKKINOS D,V,BELOGIANNEAS C.Left Ventricular remodelling:A problem in search of solutions[J].Eur Cardiol,2016,11(1):29-35.
[27] HSIAO J F,CHUNG C M,CHU C M,et al.Two-dimensional speckle tracking echocardiography predict left ventricular remodeling after acute myocardial infarction in patients with preserved ejection fraction[J].PLoS One,2016,11(12):e0168109.
[28] ECHOUFFO-TCHEUGUI J B,ERQOU S,BUTLER J,et al.Assessing the risk of progression from asymptomatic left ventricular dysfunction to overt heart failure:A systematic overview and meta-analysis[J].JACC Heart Fail,2016,4(4):237-248.
[29] DEL-BUONO M G,MORONI F,MONTONE R A,et al.Ischemic cardiomyopathy and heart failure after acute myocardial infarction[J].Curr Cardiol Rep,2022,24(10):1505-1515.
[30] ZHANG Z,CHEN Y,ZHENG L,et al.A DUSP6 inhibitor suppresses inflammatory cardiac remodeling and improves heart function after myocardial infarction[J].Dis Model Mech,2023,16(5):dmm049662.
[31] LEI C,TAN Y,NI D,et al.cGAS-STING signaling in ischemic diseases[J].Clin Chim Acta,2022,531:177-182.
[32] 李红娟，左征，刘海漫，等.芪苈强心胶囊联合心脏康复训练治疗心脏瓣膜病合并心力衰竭疗效及对NT-proBNP、TNF-α、IL-6水平的影响[J].现代中西医结合杂志，2021,30(16):1804-1807.
[33] LI L,LI X,ZHANG Z,et al.Protective mechanism and clinical application of hydrogen in myocardial ischemia-reperfusion injury[J].Pak J Biol Sci,2020,23(2):103-112.
[34] JADE P,MELISSA A,MATHEW J,et al.Cardiac-derived erythropoietin:A novel therapeutic strategy to treat myocardial infarction[J].FASEB J,2020,34(1):34-36.
[35] WISER C,KIM B,VINCENT J,et al.Small molecule inhibition of human cGAS reduces total cGAMP output and cytokine expression in cells[J].Sci Rep,2020,10(1):7604.
[36] YAN L S,CHENG B C,WANG Y W,et al.Xuelian injection ameliorates complete freund's adjuvant-induced acute arthritis in rats via inhibiting TLR4 signaling[J].Heliyon,2023,9(11):e21635.
[37] YAN L S,WANG L,CHENG C Y,et al.Total flavonoids from Saussurea involucrata attenuate inflammation in lipopolysaccharide-stimulated RAW264.7 macrophages via modulating p65,c-Jun,and IRF3 signaling pathways[J].Asian Pac J Trop Bio,2021,11(6):273-284.
[38] WU C,CHEN R L,WANG Y,et al.Acacetin alleviates myocardial ischaemia/reperfusion injury by inhibiting oxidative stress and apoptosis via the Nrf-2/HO-1 pathway[J].Pharm Biol,2022,60(1):553-561.
基本信息:
中图分类号:R285.5
引用信息:
[1]张焕鑫,沈祥礼,葛振嵘,等.基于cGAS-STING信号通路探讨雪莲注射液对小鼠心肌缺血再灌注损伤的保护作用[J].新疆医科大学学报,2024,47(12):1657-1664+1669.
基金信息:
新疆维吾尔自治区自然科学基金面上项目(2023D01C138)
2024-12-15
2024-12-15