Decreased PDLIM1 expression in endothelial cells contributes to the development of intracranial aneurysm

医学 基因沉默 Wnt信号通路 细胞生物学 细胞周期蛋白D1 异位表达 信号转导 体内 癌症研究 分子生物学 生物 基因 细胞周期 遗传学
作者
Yan Yan,Xuanfeng Qin,Yongtao Zheng,Tao Jin,Yuanyuan Hu,Qingzhu An,Bing Leng
出处
期刊:Vascular Medicine [SAGE]
卷期号:29 (1): 5-16
标识
DOI:10.1177/1358863x231218210
摘要

Introduction: Intracranial aneurysm (IA) is a common vascular enlargement that occurs in the wall of cerebral vessels and frequently leads to fatal subarachnoid hemorrhage. PDZ and LIM domain protein 1 (PDLIM1) is a cytoskeletal protein that functions as a platform for multiple protein complex formation. However, whether PDLIM is involved in the pathogenesis of IA remains poorly understood. Methods: Loss-of-function and gain-of-function strategies were employed to determine the in vitro roles of PDLIM1 in vascular endothelial cells (VECs). A rat model of IA was generated to study the role of PDLIM1 in vivo. Gene expression profiling, Western blotting, and dual luciferase reporter assays were performed to uncover the underlying cellular mechanism. Clinical IA samples were used to determine the expression of PDLIM1 and its downstream signaling molecules. Results: PDLIM1 expression was reduced in the endothelial cells of IA and was regulated by Yes-associated protein 1 (YAP1). Genetic silencing of PDLIM1 inhibited the viability, migratory ability, and tube formation ability of VECs. Opposite results were obtained by ectopic expression of PDLIM1. Additionally, PDLIM1 overexpression mitigated IA in vivo. Mechanistic investigations revealed that PDLIM1 promoted the transcriptional activity of β-catenin and induced the expression of v-myc myelocytomatosis viral oncogene homolog (MYC) and cyclin D1 (CCND1). In clinical settings, reduced expression of PDLIM1 and β-catenin downstream target genes was observed in human IA samples. Conclusion: Our study indicates that YAP1-dependent expression of PDLIM1 can inhibit IA development by modulating the activity of the Wnt/β-catenin signaling pathway and that PDLIM1 deficiency in VECs may represent a potential marker of aggressive disease.
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