南方医科大学学报

南方医科大学学报 ›› 2023, Vol. 43 ›› Issue (10): 1682-1688.doi: 10.12122/j.issn.1673-4254.2023.10.05

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二甲双胍减轻阿霉素诱导的心脏毒性：基于AMPK通路

魏 佳，杨 强，林 琳，朱参战，魏 瑾   

  1. 西安交通大学第二附属医院心内科，陕西 西安 710004
  • 出版日期:2023-10-20 发布日期:2023-11-02

Metformin mitigates doxorubicin-induced cardiotoxicity via the AMPK pathway

WEI Jia, YANG Qiang, LIN Lin, ZHU Canzhan, WEI Jin   

  1. Department of Cardiology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
  • Online:2023-10-20 Published:2023-11-02

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摘要： 目的 探究AMPK通路是否以及如何影响二甲双胍调节体内阿霉素心脏毒性的能力。方法 临床研究：以123例使用阿霉素进行阶段性化疗的髓系白血病、非霍奇金淋巴瘤、乳腺癌患者为研究对象，其中80例未联用二甲双胍（对照组），43例联用二甲双胍（200 mg/d，试验组）治疗。首先对两组患者进行基线资料对比，再使用自身对照及组间对照方法，回顾分析两组患者用药前后心肌损伤指标[血浆肌酸激酶同工酶（CK-MB）水平、乳酸脱氢酶（LDH）]水平及心衰相关指标[血浆B型钠尿肽（BNP）、左心室射血分数（EF）、左室短轴缩短率（FS）]等的变化。基础研究：以24只6周龄AMPKα2基因敲除小鼠（AKO）为研究对象，24只6周龄C57BL/6野生型小鼠（WT）为对照，将AKO组和WT组小鼠组内再随机分为4组，分别是对照组（Con）、二甲双胍组（MET）、阿霉素组（DOX）及二甲双胍联合阿霉素组（MET+DOX），6只/组。对上述各组小鼠行血清LDH、肌钙蛋白（I cTnI）、心肌细胞凋亡水平检测，心功能FS测定。结果 临床研究结果：两组患者化疗前血CK-MB、LDH、BNP水平及左心室EF、FS值无差别。化疗后对照组血CK-MB、LDH及BNP水平显著高于化疗前，EF及FS显著低于化疗前（P<0.05）；而试验组血CK-MB、LDH及BNP水平明显低于化疗前（P<0.05），EF及FS较化疗前无明显变化（P>0.05）。比较两组患者化疗后上述指标发现，试验组患者化疗后血CK-MB、LDH及BNP水平明显低于对照组，EF值及FS值明显高于对照组（P<0.05）。基础研究结果：心功能检测结果显示，阿霉素单药干预可使两组小鼠FS均显著降低，但AKO组FS降低程度轻于WT组（P<0.05）；二甲双胍与阿霉素共同干预，可使WT组降低的FS有所提高（P<0.05），但对AKO组降低的FS无明显改善；血清学指标检测结果显示，阿霉素单药干预可使两组小鼠LDH和cTnI均显著升高，但AKO组升高程度轻于WT组（P<0.05）；二甲双胍与阿霉素共同干预，可使WT组小鼠升高的LDH和cTnI有所降低（P<0.05），但对AKO组升高的LDH和cTnI无明显改善（P>0.05）；心肌细胞凋亡水平检测结果显示，阿霉素单药干预可使两组小鼠心肌细胞凋亡水平显著升高（P<0.01），但AKO组细胞凋亡程度轻于WT组（P<0.05）。结论 阿霉素在临床应用时可能引起患者心脏毒性作用，阿霉素联合二甲双胍后在一定程度减轻了心脏毒性，AMPK可能在二甲双胍抗阿霉素心脏毒性时发挥作用。

关键词: 阿霉素；心脏毒性；二甲双胍；AMPK通路

Abstract: Objective To explore whether metformin reduces cardiotoxicity of doxorubicin through the AMPK pathway. Methods We analyzed the data of 123 patients with myeloid leukemia, non-Hodgkin's lymphoma, or breast cancer receiving doxorubicin for phased chemotherapy, including 43 patients receiving combined treatment with metformin (test group) and 80 without metformin treatment (control group). The changes in plasma levels of CK-MB, LDH, and BNP, left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS) of the patients were observed. The effect of treatments with metformin and doxorubicin, alone or in combination, on myocardial damage, cardiac function and myocardial cell apoptosis were also observed in C57BL/6 mice with AMPKα2 gene knockout (AKO). Results CK-MB, LDH and BNP levels increased and EF and FS decreased significantly in the control group after chemotherapy (P<0.05). In the test group, CK-MB, LDH and BNP levels were significantly lowered after the combined treatment (P<0.05), while EF and FS did not undergo obvious changes (P>0.05). CK-MB, LDH and BNP levels were lower and EF and FS were higher significantly in the test group than in the control group after the treatment (P<0.05). Doxorubicin treatment reduced FS in both wild- type and AKO mice, but the reduction was less obvious in AKO group (P<0.05). The combined treatment restored FS in wild-type mice (P<0.05) but not in AKO mice. Doxorubicin significantly increased LDH and cTnI levels in both wild- type and AKO mice, but with smaller increments in the latter (P<0.05); The combined treatment with metformin reduced doxorubicin-induced elevation of LDH and cTnI levels in the wild-type mice (P<0.05) but not in AKO group (P>0.05). Doxorubicin increased myocardial cell apoptosis in both mice (P<0.01) but less strongly in AKO mice (P<0.05). Conclusion Chemotherapy with doxorubicin causes cardiotoxicity, which can be mitigated by combined treatment with metformin possibly through a mechanism involving the AMPK pathway.

Key words: doxorubicin; cardiotoxicity; metformin; AMPK