Zhang Shuai, Wang Xueping, Zhao Bingjie, Dai Tengteng, Wang Linping, Tong Lei, Zeng Qiangcheng, He Qing, Zhang Haili, Du Dongshu
International Cooperation Laboratory of Molecular Medicine, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China; College of Agriculture and Bioengineering, Heze University, Heze, Shandong, 274015, China.
School of Life Sciences, Shanghai University, Shanghai, 200444, China.
Free Radic Biol Med. 2025 Sep;237:300-311. doi: 10.1016/j.freeradbiomed.2025.06.011. Epub 2025 Jun 7.
N6-methyladenosine (m6A) modification, mediated by its associated regulatory proteins, has been increasingly recognized for its involvement in diverse pathological conditions. The rostral ventrolateral medulla (RVLM), a key vasomotor center, plays a crucial role in regulating hypertension. However, alterations in m6A and associated regulators including YTHDF3 within the RVLM, along with their functional contributions to hypertension development, remain to be fully elucidated. Here, we identified that YTHDF3 levels were significantly higher in the RVLM of SHRs than in WKY rats. YTHDF3 knockdown in the RVLM of SHRs reduced neuronal excitability, sympathetic tone, and blood pressure (BP). Mechanistically, YTHDF3 promoted the degradation of XRCC1 mRNA in an m6A-dependent manner. YTHDF3 silencing increased XRCC1 expression, facilitating the repair of neuronal DNA oxidative damage and suppressing neuronal apoptosis in vitro and in vivo. These beneficial effects were abrogated by XRCC1 inhibition. Notably, XRCC1 downregulation significantly reversed the suppressive effects on RVLM neuronal excitability, sympathetic tone, and BP in SHRs caused by YTHDF3 repression. The study established, for the first time, the significance of YTHDF3 as a key regulatory factor in the neural regulation of hypertension. Targeting the YTHDF3-XRCC1 axis in the RVLM represents a promising therapeutic strategy for hypertension.
N6-甲基腺苷（m6A）修饰由其相关调节蛋白介导，因其参与多种病理状况而越来越受到认可。延髓头端腹外侧区（RVLM）是关键的血管运动中枢，在调节高血压中起关键作用。然而，RVLM内m6A及包括YTHDF3在内的相关调节因子的改变及其对高血压发展的功能作用仍有待充分阐明。在此，我们发现SHR大鼠RVLM中YTHDF3水平显著高于WKY大鼠。在SHR大鼠的RVLM中敲低YTHDF3可降低神经元兴奋性、交感神经张力和血压（BP）。机制上，YTHDF3以m6A依赖的方式促进XRCC1 mRNA的降解。YTHDF3沉默增加了XRCC1表达，在体外和体内均促进了神经元DNA氧化损伤的修复并抑制了神经元凋亡。这些有益作用被XRCC1抑制所消除。值得注意的是，XRCC1下调显著逆转了YTHDF3抑制对SHR大鼠RVLM神经元兴奋性、交感神经张力和血压的抑制作用。该研究首次确立了YTHDF3作为高血压神经调节关键调节因子的重要性。靶向RVLM中的YTHDF3-XRCC1轴代表了一种有前景的高血压治疗策略
