RNF13 protects against pathological cardiac hypertrophy through p62-NRF2 pathway

• Published in: Free radical biology & medicine Vol. 209; no. Pt 2; pp. 252 - 264
• Main Authors: Guo, Sen, Zhang, Bin-Bin, Gao, Lu, Yu, Xiao-Yue, Shen, Ji-Hong, Yang, Fan, Zhang, Wen-Cai, Jin, Ya-Ge, Li, Gang, Wang, Yan-Ge, Han, Zhan-Ying, Liu, Yuan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.11.2023
• Subjects: Animals; Cardiac hypertrophy; Cardiomegaly - metabolism; Heart Failure - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NRF2; Oxidative stress; p62; RNF13; Signal Transduction; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Cardiac hypertrophy; Oxidative stress; RNF13; NRF2; p62
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2023.10.395

Heart failure (HF) severely impairs human health because of its high incidence and mortality. Cardiac hypertrophy is the main cause of HF, while its underlying mechanism is not fully clear. As an E3 ubiquitin ligase, Ring finger protein 13 (RNF13) plays a crucial role in many disorders, such as liver immune, neurological disease and tumorigenesis, whereas the function of RNF13 in cardiac hypertrophy remains largely unknown. In the present study, we found that the protein expression of RNF13 is up-regulated in the transverse aortic constriction (TAC)-induced murine hypertrophic hearts and phenylephrine (PE)-induced cardiomyocyte hypertrophy. Functional investigations indicated that RNF13 global knockout mice accelerates the degree of TAC-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis and heart dysfunction. On the contrary, adeno-associated virus 9 (AAV9) mediated-RNF13 overexpression mice alleviated cardiac hypertrophy. Furthermore, we demonstrated that adenoviral RNF13 attenuates the PE-induced cardiomyocyte hypertrophy and down-regulates the expression of cardiac hypertrophic markers, while the opposite results were observed in the RNF13 knockdown group. The RNA-sequence of RNF13 knockout and wild type mice showed that RNF13 deficiency activates oxidative stress after TAC surgery. In terms of the mechanism, we found that RNF13 directly interacted with p62 and promoted the activation of downstream NRF2/HO-1 signaling. Finally, we proved that p62 knockdown can reverse the effect of RNF13 in cardiac hypertrophy. In conclusion, RNF13 protects against the cardiac hypertrophy via p62-NRF2 axis. [Display omitted] •RNF13 inhibits the development of pathological cardiac hypertrophy.•RNF13 is involved in the process of anti-oxidative stress in cardiac hypertrophy.•p62-NRF2 signaling pathway is necessary for RNF13 to regulate the cardiac hypertrophy.