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Novel Epigenetic Mechanisms of Endogenous CSE/H₂S in Smooth Muscle Cells for Abdominal Aortic Aneurysm

ABSTRACT: Background: The incidence of abdominal aortic aneurysm is increasing year by year. Its rupture is associated with a high mortality rate, and recurrence is extremely likely even after treatment. The gasotransmitter hydrogen sulfide (H₂S) and its key generating enzyme, cystathionine -γ -lyase (CSE), possess anti -inflammatory, antioxidant, and anti -apoptotic properties, and have a cardiovascular protective effect. However, the role of CSE in AAA development and progression remains elusive. Methods: Using smooth muscle cell-specific CSE-knockout mice as models and angiotensin II, β-aminopropionitrile as inducers, it was found that CSE knockout in smooth muscle cells increased AAA incidence and mortality. Experimental results confirmed smooth muscle endogenous CSE/H₂S is involved in AAA development. However, its molecular mechanism remains a key scientific issue urgently needing solution. Thus, whole-genome RNA sequencing analysis was carried out on primary aortic smooth muscle cells isolated from Ang II-stimulated C57BL/6J mice (CSE WT) and global CSE-knockout mice (CSE KO) to identify potential key downstream genes regulated by CSE. Results: The RNA - seq data highlighted the crucial role of CSE in the regulation of extracellular matrix and the PRC complex, which has implications for the development of AAA.

ORGANISM(S): Mus musculus

PROVIDER: GSE290627 | GEO | 2026/02/19

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.

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Novel Epigenetic Mechanisms of Endogenous CSE/H₂S in Smooth Muscle Cells for Abdominal Aortic Aneurysm

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