Jiang Chuan, Ye Jiasen, Huang Jie, Gao Yang, Chen Hong, Guo Fuqiang, Guo Lei, Yuan Xiaofan
Department of General Practice, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Department of Neurosurgery, Southwest Medical University, Luzhou, Sichuan, China.
Front Cell Dev Biol. 2025 Jun 18;13:1592594. doi: 10.3389/fcell.2025.1592594. eCollection 2025.
In-stent restenosis (ISR) remains a significant public health challenge globally, as millions of stents are implanted annually. Elucidating the mechanisms underlying ISR is essential for developing effective preventive and therapeutic strategies. In this study, we identified SOX9, a transcription factor, as a key factor involved in the pathogenesis of ISR. Morphological and histological analyses of human carotid atherosclerotic plaques revealed high expression of SOX9 at the interface between the fibrous cap (FC)-predominantly composed of α-smooth muscle actin (α-SMA)-positive vascular smooth muscle cells (VSMCs)-and the lipid-rich necrotic core (LRNC), enriched with CD68-positive macrophages. This region is characterized by a high frequency of phenotypic transformation of VSMCs. Using a carotid artery balloon injury model, we observed high expression of SOX9 in the neointima, and SOX9 knockdown significantly attenuated intimal hyperplasia. , SOX9 knockdown in primary VSMCs suppressed platelet-derived growth factor-BB (PDGF-BB)-induced phenotypic transformation, proliferation, and migration. Further studies using CUT&Tag analysis indicated that PDGF-BB promotes the AMPK signaling pathway, leading to the nuclear translocation of SOX9. A dual-luciferase reporter assay revealed that SOX9 directly binds to the motif of the signal transducer and activator of transcription 3 (STAT3) promoter, thereby enhancing the phenotypic transformation of VSMCs. This study uncovered a novel molecular mechanism in which AMPK-mediated SOX9 activation facilitates its interaction with STAT3 to regulate the transformation, proliferation, and migration of VSMCs. These findings suggest that targeting the SOX9-STAT3 axis can serve as a promising therapeutic strategy for the prevention and treatment of ISR.
支架内再狭窄（ISR）在全球范围内仍然是一项重大的公共卫生挑战，因为每年有数百万个支架被植入。阐明ISR的潜在机制对于制定有效的预防和治疗策略至关重要。在本研究中，我们确定转录因子SOX9是参与ISR发病机制的关键因素。对人类颈动脉粥样硬化斑块的形态学和组织学分析显示，在主要由α平滑肌肌动蛋白（α-SMA）阳性血管平滑肌细胞（VSMC）组成的纤维帽（FC）与富含CD68阳性巨噬细胞的富含脂质的坏死核心（LRNC）之间的界面处，SOX9表达较高。该区域的特征是VSMC的表型转化频率较高。使用颈动脉球囊损伤模型，我们观察到新生内膜中SOX9表达较高，并且SOX9基因敲低显著减轻内膜增生。此外，原代VSMC中的SOX9基因敲低抑制了血小板衍生生长因子-BB（PDGF-BB）诱导的表型转化、增殖和迁移。使用CUT&Tag分析的进一步研究表明，PDGF-BB促进AMPK信号通路，导致SOX9核转位。双荧光素酶报告基因检测显示，SOX9直接结合信号转导和转录激活因子3（STAT3）启动子的基序，从而增强VSMC的表型转化。本研究揭示了一种新的分子机制，即AMPK介导的SOX9激活促进其与STAT3的相互作用，以调节VSMC的转化、增殖和迁移。这些发现表明，靶向SOX9-STAT3轴可作为预防和治疗ISR的一种有前景的治疗策略。
