Novel Roles of Nrf3-Trim5 Axis in Vascular Smooth Muscle Cell Dysfunctions and Neointimal Hyperplasia

Neointimal hyperplasia (NIH), driven by vascular smooth muscle cell (VSMC) dysfunction, is a key factor in vascular diseases like atherosclerosis and restenosis. While Nrf3 is known to regulate VSMC differentiation, its role in NIH remains unclear. Using transcriptomic data, Nrf3 knockout mice (global), we assessed Nrf3’s impact on VSMC function and NIH. We identified Trim5, a gene linked to coronary artery disease, as a downstream target of Nrf3, which promotes autophagy in VSMCs and injured arteries, enhancing VSMC dysfunction and NIH. Nrf3 overexpression increased VSMC proliferation, migration, and inflammation, while deletion or knockdown had the opposite effects. Nrf3-/- and Nrf3ΔSMC mice showed reduced VSMC accumulation and attenuated NIH after vascular injury. These findings highlight Nrf3 as a novel modulator of VSMC dysfunction and injury-induced NIH, with potential for therapeutic targeting of the Nrf3-Trim5 axis to treat NIH-related vascular diseases. Arterial injury was induced using femoral artery wire injury and carotid artery ligation model (Nrf3 knockout mice (Nrf3-/-) and control groups (flox mice). Tissue samples were collected at the seventh day post-injury for RNA extraction. RNA-seq libraries were prepared from total RNA using a standard mRNA enrichment protocol, followed by high-throughput sequencing on an Illumina platform. Paired-end sequencing (150 bp) was performed to generate high-quality transcriptomic data. Differential gene expression analysis was performed to identify genes affected by Nrf3 deletion, focusing on pathways related to VSMC dysfunction and injury-induced neointimal hyperplasia (NIH).