Vascular restenosis following paclitaxel-coated balloon therapy is attributable to NLRP3 activation and LIN9 upregulation

Abstract

Abstract Lower limb arterial occlusive disease is treated with intraluminal devices, such as paclitaxel (PTX)-coated balloons (PCBs); however, post-procedural restenosis remains a significant challenge. NLRP3 activation is known to play a significant role in atherosclerosis, but its involvement in restenosis following PCB intervention remains to be investigated. We identified that NLRP3 was differentially expressed in lower-limb arterial tissues sourced from healthy controls and patients with arterial occlusive disease. Through cell experiments, we confirmed that PTX is involved in the activation of NLRP3. Subsequently, we demonstrated that NLRP3 activation promotes the proliferation and migration of vascular smooth muscle cell (VSMC), thereby reducing their sensitivity to PTX. NLRP3 activation also stimulates the secretion of the inflammatory cytokine interleukin IL-1β. RNA sequencing of IL-1β-treated VSMC revealed the upregulation of BRD4 and LIN9. Further mechanistic investigations confirmed that IL-1β facilitates BRD4 recruitment, leading to enhanced LIN9 expression. The transcription factor LIN9 binds to the promoter region of the cell-cycle regulator AURKA, thereby promoting its transcription and subsequently upregulating the expression of the cell proliferation-associated molecule FOXM1. These processes ultimately mediate the proliferation, migration, and PTX resistance of VSMC. Additionally, we discovered that JQ1 inhibited the overexpression of the above molecules, and exhibited a synergistic effect with PTX. Our conclusions were validated through in vivo experiments in Sprague-Dawley rats. Collectively, our findings provide insights into the molecular mechanisms underlying restenosis following PCB therapy, and suggest that the combined use of JQ1 and PTX devices may represent a promising therapeutic strategy. Graphical Abstract

Keywords

• Vascular restenosis
• Paclitaxel-coated balloon
• NLRP3
• LIN9