PI3K/Akt信号通路在Irisin抵抗阿霉素心肌毒性中的作用

卢林鹤; 马继鹏; 李兰兰; 唐嘉佑; 金屏; 丁鹏; 刘洋; 杨丽芳; 俞世强; 杨剑

doi:10.12125/j.chj.201906037

PI3K/Akt信号通路在Irisin抵抗阿霉素心肌毒性中的作用

Protective role of irisin against doxorubicin cardiotoxicity injury via PI3K/Akt signaling pathway

摘要

摘要:
目的探究鸢尾素（Irisin）能否通过调控PI3K/Akt信号通路减轻阿霉素（Doxorubicin, Dox）心肌细胞毒性及其分子机制。
方法将培养的H₉C₂细胞随机分为：对照（Con）组、Irisin处理（Irisin）组、Dox损伤（Dox）组、Dox + Akt抑制剂（Dox + LY294002）组、Irisin保护（Dox + Irisin）组、Dox + Irisin+Akt抑制剂（Dox + Irisin + LY294002）组。分别采用原位切口末端标记法（TUNEL）检测细胞凋亡率、Western Blot检测凋亡相关蛋白表达水平以及CCK-8试剂检测细胞活力，明确Irisin处理对Dox诱导的心肌凋亡的作用。
结果体外实验证明，与Con组细胞相比，Dox处理后H₉C₂细胞凋亡率显著增加，并且凋亡相关蛋白Bax、Cleaved-caspase 3的表达显著增加，同时抗凋亡蛋白Bcl-2的表达量显著降低（P < 0.05），而加入Irisin可显著逆转Dox导致的心肌细胞凋亡率增加和凋亡相关蛋白质的表达趋势。进一步的研究证实，Irisin通过促进Akt的磷酸化而上调PI3K/Akt信号通路，从而降低H₉C₂细胞的凋亡，而加入Akt抑制剂LY294002后，Irisin对Dox诱导的心肌细胞毒性的缓解作用被削弱，并且促凋亡相关蛋白的表达量也显著升高。
结论 Irisin可能通过上调PI3K/Akt信号通路抑制细胞凋亡，降低Dox诱导的心肌细胞毒性，为临床治疗Dox心肌损伤提供潜在的药物靶点和治疗策略。

Abstract:
AIM To investigate whether irisin could regulate the PI3K/Akt signaling pathway to attenuate doxorubicin (Dox)-induced cardiotoxicity and its molecular mechanism.
METHODS H₉C₂ cells were cultured and randomly divided into the following groups: control (Con) group, irisin treatment (Irisin) group, Dox injury (Dox) group, Dox+Akt inhibitor (Dox+LY294002) group, irisin protection (Dox+Irisin) group, and Dox+Irisin+Akt inhibitor (Dox+Irisin+LY294002) group. TUNEL (TdT-mediated dUTP Nick-End Labeling), Western Blot and CCK-8 reagent were used to detect the apoptosis ratio, the expression of apoptotic related proteins and the cell viability respectively, which will further clarify the functions of irisin treatment against Dox-induced cardiotoxicity.
RESULTS The apoptosis rate of H₉C₂ cardiomyocytes was significantly increased after Dox treatment compared with the Con group. The expressions of Bax and Cleaved-caspase3 were significantly increased while the expression of Bcl-2 was significantly decreased (P<0.05), which were reversed by irisin treatment. In vitro experiments further demonstrated that irisin had a protective role against doxorubicin cardiotoxicity injury by increasing the phosphorylation of Akt, which was impaired by the PI3K inhibitor, LY294002.
CONCLUSION Irisin attenuates Dox-induced cardiotoxicity by the activation of PI3K/Akt signaling pathway, which may clinically provide new therapeutic targets and strategies against Dox-induced cardiotoxicity.

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