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<p>Abdominal aortic aneurysm (AAA) and the attendant catastrophic event of rupture remain a leading cause of death. Germline mutation of <i>RRAS2</i> cause Noonan Syndrome, yet little is known about its function in AAA pathogenesis. Integrated analysis of RNA-seq data revealed <i>RRAS2</i> 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 <i>Rras2</i> were more vulnerable to Ang II and porcine pancreatic elastase-induced AAA, while overexpression of <i>Rras2</i> in SMCs inhibited AAA progression. Maternally expressed gene 3 (MEG3) prevented <i>RRAS2</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Shanshan Luo,
  • Jiyu Chen,
  • Ke Zhong,
  • Xiaoqi Wu,
  • Rui Li,
  • Tianyu Song,
  • Zhongxu Sun,
  • Shixiu 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

摘要

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.