卡格列净对阿霉素所致心肌细胞损伤的作用及机制研究  

Effects and Mechanisms of Canagliflozin on Doxorubicin-Induced Cardiomyocyte Injury

作　　者：沈鐲钰 黄丹[1] 赵淑红 马振国[1] SHEN Zhuoyu;HUANG Dan;ZHAO Shuhong;MA Zhengguo(Department of Cardiology,Renmin Hospital of Wuhan University,Hubei Key Laboratory of Metabolic and Chronic Diseases,Wuhan 430060,Hubei,China)

机构地区：[1]武汉大学人民医院心血管内科代谢与相关慢病湖北省重点实验室,湖北武汉430060

出　　处：《心血管病学进展》2025年第3期272-277,共6页Advances in Cardiovascular Diseases

基　　金：国家自然科学基金青年科学基金(81700254);湖北省青年拔尖人才项目。

摘　　要：目的 研究卡格列净(CANA)对阿霉素(DOX)诱导的心肌细胞损伤的影响及其作用机制。方法 使用1μmol/L DOX构建原代大鼠心肌细胞损伤模型,构建CANA浓度梯度(1、5、10、20和30μmol/L)与DOX共刺激后,利用CCK-8法检测心肌细胞活力,结果显示当CANA浓度为10μmol/L时细胞活力恢复最明显,后续实验CANA浓度均采用10μmol/L;将原代大鼠心肌细胞随机分为4组,分别是对照组、CANA组、DOX组、DOX+CANA组;使用酶联免疫吸附试验检测乳酸脱氢酶、肌酸激酶同工酶、超氧化物歧化酶、过氧化氢酶和丙二醛含量,蛋白质印迹法检测B淋巴细胞瘤-2(Bcl-2)、Bcl-2相关X蛋白、裂解型半胱氨酸天冬氨酸蛋白酶-3、蛋白激酶B和糖原合成酶激酶-3β的表达,TUNEL染色验证细胞凋亡,实时荧光定量聚合酶链反应检测白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α转录水平。结果 和对照组比较,DOX组心肌细胞活性显著降低,且心肌损伤标志物水平显著升高(P<0.05);细胞凋亡增加,Bcl-2相关X蛋白、裂解型半胱氨酸天冬氨酸蛋白酶-3以及丙二醛水平明显升高(P<0.05),而Bcl-2水平、过氧化氢酶以及超氧化物歧化酶活性显著降低(P<0.05);炎症反应增强,白细胞介素-1β、白细胞介素-6及肿瘤坏死因子-α转录水平显著上调(P<0.05);蛋白激酶B和糖原合成酶激酶-3β表达被明显抑制(P<0.05)。与DOX组比较,DOX+CANA组心肌细胞活性明显增加,且心肌损伤标志物水平降低(P<0.05);细胞凋亡减少,Bcl-2相关X蛋白、裂解型半胱氨酸天冬氨酸蛋白酶-3以及丙二醛水平明显下降(P<0.05),而Bcl-2水平、过氧化氢酶以及超氧化物歧化酶活性显著增加(P<0.05);炎症反应减弱,白细胞介素-1β、白细胞介素-6及肿瘤坏死因子-α转录水平明显下调(P<0.05);蛋白激酶B和糖原合成酶激酶-3β表达水平显著升高(P<0.05)。结论 CANA可通过抑制氧化应激、减轻炎症反应、抑制细胞凋亡以�Objective To investigate the effects of canagliflozin(CANA) on doxorubicin(DOX)-induced cardiomyocyte injury and its underlying mechanisms.Methods Primary neonatal rat cardiomyocyte injury model was established using 1 μmol/L DOX.A gradient of CANA concentrations(1,5,10,20,30 μmol/L) was co-administered with DOX,and cell viability was assessed by the CCK-8 assay,the results indicated that cell viability was most prominently restored at a CANA concentration of 10 μmol/L,and henceforth,a concentration of 10 μmol/L was employed for CANA in all subsequent experiments.Primary neonatal rat cardiomyocytes were randomly divided into four groups:negative control,CANA,DOX,and DOX+CANA.Enzyme linked immunosorbent assay was employed to measure lactate dehydrogenase,creatine kinase isoenzyme,superoxide dismutase,catalase,and malondialdehyde levels.Western blotting was used to detect the expression of B-cell lymphoma-2(Bcl-2),Bcl-2-associated X,cleaved caspase-3,protein kinase B and glycogen synthase kinase-3β.TUNEL staining was used to confirm apoptosis,and real-time quantitative polymerase chain reaction was used to quantify the transcription levels of interleukin-1β,interleukin-6,and tumor necrosis factor-α.Results Compared with the negative control group,the DOX group showed significantly reduced cell viability and elevated levels of myocardial injury markers(P<0.05).Increased apoptosis,along with heightened levels of Bcl-2-associated X,cleaved caspase-3,and malondialdehyde was observed,while Bcl-2 levels,catalase activity,and superoxide dismutase activity were notably reduced(P<0.05).Enhanced inflammatory response was evidenced by significantly upregulated transcription of interleukin-1β,interleukin-6,and tumor necrosis factor-α(P<0.05),accompanied by suppressed protein kinase B/glycogen synthase kinase-3β expression(P<0.05).In contrast,the DOX+CANA group demonstrated increased cell viability,reduced myocardial injury marker levels,decreased apoptosis,lowered Bcl-2-associated X,cleaved caspase-3,and malondialdeh

关 键 词：卡格列净 阿霉素 炎症 凋亡 氧化应激 蛋白激酶B 

分 类 号：R73[医药卫生—肿瘤]