[1]沈鐲钰 黄丹 赵淑红 马振国.卡格列净对阿霉素所致心肌细胞损伤的作用及机制研究[J].心血管病学进展,2025,(3):272.[doi:10.16806/j.cnki.issn.1004-3934.2025.03.017]
　SHEN Zheyu,HUANG Dan,ZHAO Shuhong,et al.Canagliflozin’s Role in Ameliorating Doxorubicin-Induced Injury in Cardiomyocytes[J].Advances in Cardiovascular Diseases,2025,(3):272.[doi:10.16806/j.cnki.issn.1004-3934.2025.03.017]
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卡格列净对阿霉素所致心肌细胞损伤的作用及机制研究()
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《心血管病学进展》[ISSN:51-1187/R/CN:1004-3934]

卷:
期数:
2025年3期
页码:
272
栏目:
论著
出版日期:
2025-03-25

文章信息/Info

Title:
Canagliflozin’s Role in Ameliorating Doxorubicin-Induced Injury in Cardiomyocytes
作者:
沈鐲钰 黄丹 赵淑红 马振国
(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 )
Author(s):
SHEN Zheyu; 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)
关键词:
卡格列净; 阿霉素; 炎症; 凋亡; 氧化应激; 蛋白激酶B
Keywords:
Canagliflozin; Doxorubicin; Inflammation; Apoptosis; Oxidative stress; Protein kinase B
DOI:
10.16806/j.cnki.issn.1004-3934.2025.03.017
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1 μmol/LDOX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30 μmol/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10 μmol/L时细胞活力恢复最明显，后续实验CANA浓度均采用10 μmol/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组心肌细胞活力显著降低，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/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组心肌细胞活力明显增加，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/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、抑制细胞凋亡以及调控蛋白激酶B信号通路来减轻DOX诱导的心肌细胞损伤。
Abstract:
Objective To investigate the effects of canagliflozin （CANA） on doxorubicin（DOX）-induced cardiomyocyte injury and its underlying mechanisms. Methods P rimary neonatal rat cardiomyoc yte inj ury 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, t he 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 :Control,CANA,DOX,and DOX+CANA. Enzyme linked immunosorbent assay was employed to measure lactate dehydro genase,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 quantif y the transcription levels of i nterleukin-1β,interleukin-6,and tumor necrosis factor-α. Results Compared with the 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 i nterleukin-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 malondialdehyde levels,and elevated Bcl-2 levels ,catalase activity ,and superoxide dismutase activity compared to the DOX group ( P＜0.05). The inflammatory response was attenuated,with transcription levels of interleukin-1β ,interleukin-6,and tumor necrosis factor-α significantly downregulated .The expression levels of protein kinase B/glycogen synthase kinase-3β are significantly increased ( P＜0.05). Conclusion CANA alleviates DOX-induced cardiomyocyte damage through inhibiting oxidative stress,mitigating inflammation,suppressing apoptosis,and modulating the protein kinase B signaling pathway.

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更新日期/Last Update: 2025-04-29