Novel roles of Nrf3–Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia

作者：Qishan Chen, Shasha Sun, Zhenning Shi, Leyu Wang, Yumeng Wang, Ancheng Zheng, Xiaolei Xu, Mei Yang, Kun Sun, Qingzhong Xiao, Li Zhang · 发表于：Cardiovascular Research · 年份：2025 · DOI：10.1093/cvr/cvaf084 · 被引用次数：5 · 研究领域：Genomics, phytochemicals, and oxidative stress、Endoplasmic Reticulum Stress and Disease、Autophagy in Disease and Therapy

AIMS: Neointimal hyperplasia (NIH) characterized by vascular smooth muscle cell (VSMC) dysfunctions plays a critical role in many vascular diseases including atherosclerosis and restenosis, which leads to serious ischaemic complications and has limited therapeutic approaches. Our previous studies confirm a critical role for nuclear factor erythroid 2-related factor 3 (Nrf3) in VSMC differentiation. However, little is known about the functional implications of Nrf3 in NIH. METHODS AND RESULTS: Transcriptome dataset and human atherosclerotic samples were used to determine Nrf3 expression levels. Global (Nrf3-/-) and VSMC-specific (Nrf3ΔSMC) Nrf3 knockout mice were used to assess the role of Nrf3 in VSMC function and injury-induced NIH. Complementary molecular methods were performed to identify Nrf3 downstream targets and elucidate the regulatory role of Nrf3 in target gene regulation. Porcine carotid stenting model was used to validate the therapeutic effects of Nrf3 inhibition in vascular remodelling. Transcriptomic data and immunostaining analysis showed increased levels of Nrf3, and a positive correlation between Nrf3 and NIH in the human atherosclerotic vessels. Various pathophysiological stimuli induced endoplasmic reticulum stress that enhanced Nrf3 expression via Activating Transcription Factor 4 (ATF4). Nrf3 overexpression promoted both human and mouse VSMC proliferation, migration, and inflammatory response, while opposite effects were observed when Nrf3 was deleted or...