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

Area of Science:

• Vascular Biology
• Genetics
• Molecular Medicine

Background:

• Abdominal aortic aneurysm (AAA) rupture is a major cause of mortality.
• The role of RRAS2 in AAA pathogenesis is largely unknown.
• RRAS2 mutations are linked to Noonan Syndrome.

Purpose of the Study:

• To investigate the role of RRAS2 in AAA.
• To elucidate the molecular mechanisms underlying RRAS2's function in vascular smooth muscle cells (VSMCs).

Main Methods:

• Integrated analysis of RNA-seq data from AAA patients and mice.
• Generation of SMCs-specific Rras2 knockout and overexpression mouse models.
• Angiotensin II (Ang II) and porcine pancreatic elastase-induced AAA models.
• Investigation of the interaction between MEG3, ELAVL1, and RRAS2.
• Analysis of GTF2-I phosphorylation, nuclear translocation, and transcriptional activity.

Main Results:

• RRAS2 mRNA and protein levels are decreased in AAA.
• SMCs-specific Rras2 knockout mice exhibit increased vulnerability to AAA induction.
• Overexpression of RRAS2 inhibits AAA progression.
• MEG3 stabilizes RRAS2 mRNA by inhibiting its degradation via ELAVL1.
• Loss of R-Ras2 impairs GTF2-I activity, reducing contractile gene expression.

Conclusions:

• RRAS2 plays a critical protective role in maintaining VSMC homeostasis.
• RRAS2 is a potential therapeutic target for preventing AAA progression.