The circular RNA circNlgnmediates doxorubicin-inducedcardiac remodeling and fibrosis

Jindong Xu; William W Du; Nan Wu; Feiya Li; Xiangmin Li; Yizhen Xie; Sheng Wang; Burton B Yang

doi:10.1016/j.omtn.2022.03.007

The circular RNA circNlgnmediates doxorubicin-inducedcardiac remodeling and fibrosis

Mol Ther Nucleic Acids. 2022 Mar 9:28:175-189. doi: 10.1016/j.omtn.2022.03.007. eCollection 2022 Jun 14.

Authors

Jindong Xu^{1

2

3}, William W Du¹, Nan Wu¹, Feiya Li^{1

4}, Xiangmin Li^{1

5}, Yizhen Xie⁵, Sheng Wang^{2

3}, Burton B Yang^{1

4

6}

Affiliations

¹ Sunnybrook Research Institute, Sunnybrook Health Sciences Centres, Toronto, ON, Canada.
² Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Cardiovascular Institute, Guangzhou, Guangdong Province, China.
³ The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, China.
⁴ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁵ Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, Guangdong Province, China.
⁶ Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Abstract

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.

Keywords: RNA-seq; cardiac fibrosis; cardiac remodeling; circNlgn; circRNA; circular RNA; doxorubicin; heart function.