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

ABSTRACT: Abdominal aortic aneurysm (AAA) and the attendant catastrophic event of rupture remain a leading cause of death. During AAA, VSMCs lost contractile-related phenotype, with reduced levels of actin alpha 2, smooth muscle (ACTA2), transgelin (TAGLN) and calponin 1 (CNN1)) , and obtain ability to secrete matrix metalloproteinases to degrade the extracellular matrix and weaken the arterial wall, which potentiate the rupture of the aneurysm. Angiotensin 2 (Ang II) can induce phenotype transition of VSMCs，while the underlying mechanism remains elusive. Here we found Ang II treatment could reduce expression of R-Ras2, thus reducing the phosphorylation and nuclear translocation of TFII-I, as a result, the gene expression of ACTA2, TAGLN and CNN1 were inhibited and VSMCs lost the contractile phenotype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291516 | GEO | 2025/06/29

REPOSITORIES: GEO

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Project description:Background: Abdominal aortic aneurysm (AAA) is a potentially life-threatening condition, but approved medical therapies to prevent AAA progression and rupture are currently lacking. Sphingolipids metabolism disorders are associated with the occurrence and development of AAA. It has been discovered that ganglioside GM3, a sialic acid-containing type of glycosphingolipid, plays a protective role in atherosclerosis which is an important risk factor for AAA, but the potential contribution of GM3 to AAA development has not been investigated. Methods: We performed a metabolomics study to evaluated GM3 level in plasma of human AAA patients. We profiled GM3 synthase (ST3GAL5) expression in the mouse model of aneurysm and human AAA tissues through western blotting and immunofluorescence staining. RNA sequencing, proteomic analysis, affinity purification and mass spectrometry, surface plasmon resonance (SPR) analysis, and functional studies were used to dissect the molecular mechanism of GM3-regulating ferroptosis. We conditionally deleted and overexpressed St3gal5 in smooth muscle cells (SMCs) in vivo to investigate its role in AAA. Results: We found significantly reduced plasma levels of the GM3 in human AAA patients. GM3 content and ST3GAL5 expression were all decreased in abdominal aortic VSMCs in AAA patients and mouse model. RNA-sequencing analysis showed that ST3GAL5 silencing in human aortic SMCs (HASMCs) induced ferroptosis. Importantly, we showed that GM3 interacted directly with the extracellular domain of transferrin receptor 1 (TFR1), a cell membrane protein critical for cellular iron uptake, disrupted its interaction with holo-transferrin. SMC-specific St3gal5 knockout exacerbated iron accumulation at lesion sites and significantly promoted AAA development, while GM3 supplementation suppressed lipid peroxidation, reduced iron deposition in aortic VSMCs and markedly decreased AAA incidence. Conclusions: Together, these results suggest that GM3 dysregulation promotes ferroptosis of VSMCs in AAA. Furthermore, GM3 may constitute a new therapeutic target for the treatment of AAA.

Project description:Aims Abdominal aortic aneurysm (AAA) is a complex aortic disease define by a dilatation of the infrarenal aorta and the most common form of aneurysm in humans. Whereas inflammation contribute to AAA development, quenching vascular inflammation using classical pharmacological approaches or inhibiting the immune system does not influence the progression of AAA in humans indicating the lack of a complete picture on the molecular events that drive this aortopathy. This study was designed to comprehend the earliest molecular indicators, aiming to pinpoint a biological target associated with the latter. Methods and results Using ApoE-deficient mice fed with a standard diet and infused with Angiotensin II (Ang II), we conducted bulk RNA-sequencing analysis on suprarenal (SRA) regions obtained from both unchallenged and challenged WT mice, specifically examining responses 24 hours after Ang II infusion to capture the initial phases of aortic stress response. We further created a unique model of hyperlipidemic mice in which the expression of IKK can be conditionally (via tamoxifen injection) suppressed in vascular SMCs (CreERT2 under the control of the Acta2 promoter). The development of AAA was evaluated using in situ examination and quantified using RT-qPCR, immunohistochemistry and fluorescence microscopy. Cultured vascular SMC were exposed to the selective IKK inhibitor MLN120b and the expression levels of phenotypic markers KLF4, -Catenin and CTGF were addressed using cellular extracts and immunoblot analysis. Results RNASeq data support the presence of early anabolic events in SRA regions detailing activation of the mTORC1 pathway, which paralleled cellular processes including mitochondria, ribosome and sterol biosynthesis and the Unfolded Protein Response (UPR). Conditional deletion of the Ikbkb gene in vascular SMCs significantly reduces the incidence of SRA lesions as well as the rate of aneurysm ruptures in animals exposed to Ang II. In situ analysis further demonstrated that the protection conferred by the lack of IKK expression in vascular SMC is associated with reduced inflammatory response, the preservation of the contractile over the degradative vascular SMC phenotypes and the absence of anabolic and fibrotic signatures. Conclusion Our data not only reinforce the major roles play by vascular SMC in the rapid adaptation leading to the deleterious remodeling of the vascular wall and aortic lesions but also support a paradigm aiming at repositioning the efforts focusing on anabolic rather than inflammatory events.

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

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