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Leveraging cell-type specific regulatory networks to interpret genetic variations in abdominal aortic aneurysm

ABSTRACT: Abdominal aortic aneurysm (AAA) is a common degenerative cardiovascular disease without clear understanding of its pathobiology. To detect AAA associated variants that may affect gene regulation, we generated H3K27ac HiChIP data for aortic smooth muscle cells (AoSMC) and aortic endothelia cells (HAEC), the two cell types most relevant to the AAA disease. We further implemented cell type-specific REs defined from HiChIP experiments, and observed the consistency between the chromatin accessibility of REs and the expression levels of their target genes. Moreover, the cell type-specific REs contributed to detect the AAA most relevant cell type, AoSMC, and locate the important AAA-related TFs, ERG and KLF family.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178598 | GEO | 2021/11/17

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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Leveraging cell-type specific regulatory networks to interpret genetic variations in abdominal aortic aneurysm

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