Ras-related protein 2 limits vascular smooth muscle cell phenotypic switching and abdominal aortic aneurysm development

作者：Shanshan Luo, Jiyu Chen, Ke Zhong, Xiaoqi Wu, Rui Li, Tianyu Song, Zhongxu Sun, Shan-zhen Sun, Xinlong Tang, Yan Zhang, Zhi‐Ren Zhang, Bo Yu, Jinwei Tian, Li Li, Aihua Gu, Feng Chen, Dongjin Wang, Jun Pu, Yi Han, Liping Xie, Yong Ji · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-64496-7 · 被引用次数：2 · 研究领域：Aortic aneurysm repair treatments、Aortic Disease and Treatment Approaches、Nuclear Receptors and Signaling

Abdominal aortic aneurysm (AAA) and the attendant catastrophic event of rupture remain a leading cause of death. Germline mutation of RRAS2 cause Noonan Syndrome, yet little is known about its function in AAA pathogenesis. Integrated analysis of RNA-seq data revealed RRAS2 a potential regulator of AAA. Its mRNA and protein levels reduced in abdominal aorta of AAA patients and AAA mice. Mice with SMCs-specific knockout of Rras2 were more vulnerable to Ang II and porcine pancreatic elastase-induced AAA, while overexpression of Rras2 in SMCs inhibited AAA progression. Maternally expressed gene 3 (MEG3) prevented RRAS2 mRNA degradation through binding with ELAV-like protein 1 (ELAVL1/HuR). Mechanistically, loss of R-Ras2 reduces phosphorylation, nuclear translocation, and transcriptional activity of general transcription factor 2I (GTF2-I/TFII-I) to reduce contractile-related genes expression in a MET tyrosine kinase-dependent manner. Here, we show an essential role of R-Ras2 in preserving VSMCs homeostasis and provide potential therapeutic targets for AAA. This work reveals critical role of R-Ras2 in abdominal aortic aneurysm (AAA) progression. R-Ras2 maintains VSMCs function via c-MET-TFII-I axis, with MEG3 stabilizing its mRNA stability. Findings identify R-Ras2 a potential AAA therapeutic target.