Xu Jindong, Du William W, Wu Nan, Li Feiya, Li Xiangmin, Xie Yizhen, Wang Sheng, Yang Burton B
Sunnybrook Research Institute, Sunnybrook Health Sciences Centres, Toronto, ON, Canada.
Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Cardiovascular Institute, Guangzhou, Guangdong Province, China.
Mol Ther Nucleic Acids. 2022 Mar 9;28:175-189. doi: 10.1016/j.omtn.2022.03.007. eCollection 2022 Jun 14.
Doxorubicin is a chemotherapeutic medication commonly used to treat many types of cancers, but it has side effects including vomiting, rash, hair loss, and bone marrow suppression. The most dangerous side effects are cardiomyopathy, cardiofibrosis, and heart failure, as doxorubicin generates cytotoxicity and stops DNA replication. There is no treatment to block these side effects. We have developed a transgenic mouse line overexpressing the circular RNA circNlgn and shown that circNlgn is a mediator of doxorubicin-induced cardiofibrosis. Increased expression of circNlgn decreased cardiac function and induced cardiofibrosis by upregulating Gadd45b, Sema4C, and RAD50 and activating p38 and pJNK in circNlgn transgenic heart. Silencing circNlgn decreased the effects of doxorubicin on cardiac cell activities and prevented doxorubicin-induced expression of fibrosis-associated molecules. The protein (Nlgn173) translated by circNlgn could bind and activate H2AX, producing γH2AX, resulting in upregulation of IL-1b, IL-2Rb, IL-6, EGR1, and EGR3. We showed that silencing these molecules in the signaling pathway prevented doxorubicin-induced cardiomyocyte apoptosis, increased cardiomyocyte viability, decreased cardiac fibroblast proliferation, and inhibited collagen production. This mechanism may hold therapeutic implications for mitigating the side effects of doxorubicin therapy in cancer patients.
阿霉素是一种常用于治疗多种癌症的化疗药物，但它有副作用，包括呕吐、皮疹、脱发和骨髓抑制。最危险的副作用是心肌病、心脏纤维化和心力衰竭，因为阿霉素会产生细胞毒性并阻止DNA复制。目前尚无治疗方法可阻止这些副作用。我们已经培育出一种过表达环状RNA circNlgn的转基因小鼠品系，并表明circNlgn是阿霉素诱导的心脏纤维化的介质。circNlgn表达增加会降低心脏功能，并通过上调Gadd45b、Sema4C和RAD50以及激活circNlgn转基因心脏中的p38和pJNK来诱导心脏纤维化。沉默circNlgn可降低阿霉素对心脏细胞活性的影响，并预防阿霉素诱导的纤维化相关分子的表达。circNlgn翻译的蛋白质（Nlgn173）可以结合并激活H2AX，产生γH2AX，导致IL-1b、IL-2Rb、IL-6、EGR1和EGR3上调。我们表明，沉默信号通路中的这些分子可预防阿霉素诱导的心肌细胞凋亡，增加心肌细胞活力，减少心脏成纤维细胞增殖，并抑制胶原蛋白生成。这一机制可能对减轻癌症患者阿霉素治疗的副作用具有治疗意义。
