Xu Xiaoyong, Xu Xiaorong, Zhou Wangzhuo, Wang Wenwen, Lin Bin, Huang Xumei, Chen Shan
Department of Cardiology, Yongjia People's Hospital, 283 Yongjian Road, Shangtang Town, Yongjia County, Zhejiang, 325100, China.
Department of Cardiology, Wenzhou Central Hospital, Zhejiang, 325000, China.
In Vitro Cell Dev Biol Anim. 2025 Aug 13. doi: 10.1007/s11626-025-01102-6.
Atherosclerosis (AS) is a primary contributor to cardiovascular disease (CVD), resulting in high mortality. Ferroptosis, triggered by lipid peroxidation, contribute to AS development. This study aimed to explore the regulatory relationships of Trim28, ALDH4A1, P53, and ferroptosis in the pathogenesis of AS. The AS cell model was constructed by treating HUVECs with oxidized low-density lipoprotein (ox-LDL). The roles of Trim28 overexpression in regulating AS development, P53 ubiquitination, and ferroptosis of vascular endothelial cells were investigated. Moreover, the interaction between Trim28 and ALDH4A1 was explored, followed by analyzing the effect of ALDH4A1 knockdown on P53 ubiquitination. Additionally, the impact of ALDH4A1 knockdown and P53 overexpression on AS development and ferroptosis of vascular endothelial cells was explored. Reduced Trim28 expression and increased ALDH4A1 and P53 expression were observed in HUVECs after treatment with ox-LDL. Overexpression of Trim28 mitigated AS development, promoted P53 ubiquitination, and suppressed ferroptosis of vascular endothelial cells. Additionally, ALDH4A1 could interact with Trim28, and ALDH4A1 knockdown enhanced P53 ubiquitination. Moreover, P53 overexpression reversed the inhibitory effects of ALDH4A1 knockdown on AS development and ferroptosis of vascular endothelial cells. Our findings indicate that Trim28, ALDH4A1, and P53 may be key regulators in AS development. Silencing of ALDH4A1 may alleviate AS development through regulating Trim28-mediated P53 ubiquitination to inhibit ferroptosis of vascular endothelial cells. These molecules may by promising therapeutic targets for AS and related CVD.
动脉粥样硬化（AS）是心血管疾病（CVD）的主要促成因素，导致高死亡率。由脂质过氧化引发的铁死亡有助于AS的发展。本研究旨在探讨Trim28、ALDH4A1、P53和铁死亡在AS发病机制中的调控关系。通过用氧化低密度脂蛋白（ox-LDL）处理人脐静脉内皮细胞（HUVECs）构建AS细胞模型。研究了Trim28过表达在调节AS发展、P53泛素化和血管内皮细胞铁死亡中的作用。此外，探讨了Trim28与ALDH4A1之间的相互作用，随后分析了敲低ALDH4A1对P53泛素化的影响。此外，还探讨了敲低ALDH4A1和过表达P53对血管内皮细胞AS发展和铁死亡的影响。在用ox-LDL处理后的HUVECs中观察到Trim28表达降低，ALDH4A1和P53表达增加。Trim28过表达减轻了AS的发展，促进了P53泛素化，并抑制了血管内皮细胞的铁死亡。此外，ALDH4A1可以与Trim28相互作用，敲低ALDH4A1增强了P53泛素化。此外，P53过表达逆转了敲低ALDH4A1对血管内皮细胞AS发展和铁死亡的抑制作用。我们的研究结果表明，Trim28、ALDH4A1和P53可能是AS发展中的关键调节因子。敲低ALDH4A1可能通过调节Trim28介导的P53泛素化来抑制血管内皮细胞的铁死亡，从而减轻AS的发展。这些分子可能是AS和相关CVD的有前景的治疗靶点。
