期刊
EUROPEAN HEART JOURNAL
卷 43, 期 42, 页码 4496-+出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehac337
关键词
Heart failure; Circular RNA; Doxorubicin cardiotoxicity; AAVtherapy; Mitochondrial metabolism; Anti-cancer treatment
资金
- German Research Foundation, DFG [SFB/Transregio TRR267, 398066876/GRK 2485/1]
- Niedersachsische Ministerium fur Wissenschaft und Kultur, MWK (REBIRTH Anchor project)
- China Scholarship Council
This study identified a circular RNA called Circ-INSR, which is down-regulated during cardiac toxicity and remodeling. The researchers found that overexpression of Circ-INSR can prevent and reverse doxorubicin-induced cardiomyocyte death, and improve cardiac function.
Aims Cardiotoxicity leading to heart failure (HF) is a growing problem in many cancer survivors. As specific treatment strategies are not available, RNA discovery pipelines were employed and a new and powerful circular RNA (circRNA)-based therapy was developed for the treatment of doxorubicin-induced HF. Methods and results The circRNA sequencing was applied and the highly species-conserved circRNA insulin receptor (Circ-INSR) was identified, which participates in HF processes, including those provoked by cardiotoxic anti-cancer treatments. Chemotherapy-provoked cardiotoxicity leads to the down-regulation of Circ-INSR in rodents and patients, which mechanistically contributes to cardiomyocyte cell death, cardiac dysfunction, and mitochondrial damage. In contrast, Circ-INSR overexpression prevented doxorubicin-mediated cardiotoxicity in both rodent and human cardiomyocytes in vitro and in a mouse model of chronic doxorubicin cardiotoxicity. Breast cancer type 1 susceptibility protein (Brca1) was identified as a regulator of Circ-INSR expression. Detailed transcriptomic and proteomic analyses revealed that Circ-INSR regulates apoptotic and metabolic pathways in cardiomyocytes. Circ-INSR physically interacts with the single-stranded DNA-binding protein (SSBP1) mediating its cardioprotective effects under doxorubicin stress. Importantly, in vitro transcribed and circularized Circ-INSR mimics also protected against doxorubicin-induced cardiotoxicity. Conclusion Circ-INSR is a highly conserved non-coding RNA which is down-regulated during cardiotoxicity and cardiac remodelling. Adeno-associated virus and circRNA mimics-based Circ-INSR overexpression prevent and reverse doxorubicin-mediated cardiomyocyte death and improve cardiac function. The results of this study highlight a novel and translationally important Circ-INSR-based therapeutic approach for doxorubicin-induced cardiac dysfunction.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据