p62活化Nrf2信号通路拮抗阿霉素致心肌ROS-Beclin1损伤链的实验研究

基本信息
批准号:81560048
项目类别:地区科学基金项目
资助金额:38.00
负责人:晏浩
学科分类:
依托单位:南昌大学
批准年份:2015
结题年份:2019
起止时间:2016-01-01 - 2019-12-31
项目状态: 已结题
项目参与者:况晓东,张春平,蔡震宇,林辉,余群芳,朱娜,温华
关键词:
心肌毒性自由基p62Nrf2阿霉素
结项摘要

Adriamycin as first-line chemotherapy drugs is widely used in solid tumors and hematological malignancies, and induces myocardial toxicity of chemotherapy in patients with serious impact on chemotherapy tolerance and long-term survival. Depolarized mitochondria produces a large number of ROS, while Beclin1 has a detrimental effect on mitochondrial biogenesis activity and intracellular degradation mechanism by ROS, and enhances apoptosis by cleavage of Beclin-1. P62 is the activator of transcription factor Nrf2, and Nrf2 promotes transcription of p62 and endogenous antioxidants, and can inhibit indirectly the transcription and activation of Beclin1. Although the specific activation mechanism of Nrf2-mediated cardioprotection against adriamycin remains unclear, our previous study had shown that the inhibition of ROS-Beclin1 chain had protective effects in myocardium, and our pre-experiment found that doxorubicin could up-regulate the expression of Beclin1, and inhibit the nuclear translocation of Nrf2, p62 activity and autophagy flux, then siRNA knockdown of p62 exacerbated the myocardial oxidative stress injury by adriamycin. In present study, we plan to explore the mechanism that Nrf2 inhibit autophagy damage via ROS-Beclin1 Chain, and the interaction between Nrf2 and p62 by overexpression and silence, and Nrf2-p62 cardioprotection effect by improving intracellular antioxidant and mitochondria degradation mechanism to provide new target for the prevention and treatment of anthracycline cardiotoxicity.

阿霉素作为一线化疗药物广泛用于实体瘤和血液肿瘤,但其心肌毒性严重影响患者化疗的耐受程度和生存期。阿霉素致心肌线粒体受损而产生大量ROS,ROS过度激活Beclin1,Beclin1通过抑制线粒体活性、线粒体自噬降解和被剪切促进凋亡等加剧损伤。我们前期研究证实阻断ROS-Beclin1链保护病理心肌,预实验发现阿霉素上调心肌Beclin1,抑制Nrf2核转位、p62活性和自噬流,而沉默p62加剧这种损伤。已知p62是Nrf2的活化因子,而Nrf2可直接转录p62和内源抗氧化物质,并抑制Beclin1转录和活化;但活化Nrf2抗阿霉素心脏毒性作用的具体机制以及其与p62的关系尚不清楚。本研究以Nrf2活化为切入点,拟干预p62与Nrf2对话,抑制阿霉素致心肌ROS-Beclin1损伤链,阐述“Nrf2-p62”良性循环抗氧化、改善线粒体质控等保护机制,为阿霉素致心肌毒性的防治提供新的分子基础。

项目摘要

项目成果
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暂无此项成果

数据更新时间:2023-05-31

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