TET2-SLC7A1 axis regulates the proliferation, migration, and oxidative stress of vascular smooth muscle cells by NRF2 signaling in hypertension.

A growing body of evidence indicates that Ten-Eleven Translocation 2 (TET2), a modulator of DNA methylation, mediates vascular smooth muscle cells (VSMCs) undergo a phenotypic transformation in hypertension. However, the mechanisms and downstream pathways by which TET2 drives hypertension pathology require further elucidation. Accordingly, we employed protein sequencing to identify potential downstream effectors of TET2. The expression of the candidate protein SLC7A1 were verified in Control and Tet2 knockdown conditions in vivo and in vitro, as well as in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), across transcriptional, protein, and tissue-level analyses. The functional role of SLC7A1 in VSMCs (A7r5 cells) was assessed by knockdown and overexpression in VSMCs. A suite of assays was used to measure cell viability, proliferation, migration, and the levels of malondialdehyde (MDA), glutathione peroxidase (GSH), superoxide dismutase (SOD), and reactive oxygen species (ROS). Analysis revealed that SLC7A1 is a potential downstream target of TET2 and its expression was significantly downregulated in Tet2-knockdown and SHR (P < 0.01). Functionally, in VSMCs, the knockdown of SLC7A1 promoted phenotypic transformation, proliferation, migration, and oxidative stress (P < 0.05). Conversely, SLC7A1 overexpression exhibited the opposite regulatory effects (P < 0.05). Mechanistically, we found that the TET2-SLC7A1 axis exerts its biological functions through the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). In conclusion, our study defines a novel signaling pathway by which TET2 regulates VSMCs dysfunction via SLC7A1 and NRF2, thus providing advances our understanding of the pathogenesis of hypertension.