| PI3K/Akt信号通路在Irisin抵抗阿霉素心肌毒性中的作用 |
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| 引用本文： | 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. PI3K/Akt信号通路在Irisin抵抗阿霉素心肌毒性中的作用[J]. 心脏杂志, 2019, 31(6): 648-653. DOI: 10.12125/j.chj.201906037 |
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| 作者姓名： | 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 |
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| 作者单位： | 1.空军军医大学西京医院心血管外科，陕西 西安 710032 |
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| 基金项目： | 国家自然科学基金项目资助（81774415，81600295，81600240）；西京医院学科助推计划项目资助（XJZT18MJ14） |
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| 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。
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| 关 键 词： | 鸢尾素 阿霉素 心肌毒性 凋亡 PI3K/Akt |
| 收稿时间： | 2019-06-13 |
Protective role of irisin against doxorubicin cardiotoxicity injury via PI3K/Akt signaling pathway |
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| Affiliation: | 1.Department of Cardiovascular Surgery, Xijing Hospital, Air Force Medical University, Xi’an 710032, Shaanxi, China2.Department of Anesthesiology, Xi’an Children’s Hospital, Xi’an 710003, Shaanxi, China |
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| 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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