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MiRNA-378a-5p attenuates the development of abdominal aortic aneurysm via ABLIM1-MKL1 signaling pathways

ABSTRACT: Abstract Objectives: Abdominal aortic aneurysm (AAA) is a fatal cardiovascular disease with no effective drug treatment currently available. The aberrant expressions of microRNAs (miRNAs) contribute to AAA pathogenesis. In this study, we aimed to perform miRNA microarray analysis to screen for differentially expressed miRNAs in the aortas of AAA mice compared to those in control mice, and to clarify the role and mechanism of miRNA-378a-5p (miR-378a-5p) in the AAA development. Methods: We performed a comprehensive miRNA microarray analysis to screen for differentially expressed miRNAs in the aortas of AAA mice and control mice. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expressions of miR-378a-5p in the serum and aortas of AAA patients and mice. To clarify the role of miR-378a-5p in the AAA development in vivo, miR-378a-5p antagomir and angomir were administered to ApoE-/- mice using tail venous injection, followed by Angiotensin II (Ang II) infusion. Next, the role of miR-378a-5p in the phenotypic switching and migration of vascular smooth muscle cells (VSMCs) was examined in vivo and in vitro. Mechanistically, the targets of miR-378a-5p were identified by bioinformatics analysis, luciferase assay, qRT-PCR and western blot. Co-immunoprecipitation (Co-IP) assay combined with mass spectrometry were carried out for excavating potential downstream effectors. Results: The expression of miR-378a-5p was decreased in the serum and aortas of AAA patients and mice, and tumor necrosis factor-α (TNFα)-treated VSMCs. In vivo, the antagomir-378a-5p aggravated AAA formation, as evidenced by a larger maximal aortic diameter and greater medial elastin degradation than in control mice. MiR-378a-5p angomir had the opposite effect. In vitro, miR-378a-5p overexpression significantly promoted the contraction ability and suppressed the migration of VSMCs, whereas miR-378a-5p knockdown inhibited the contraction ability and increased the migration of VSMCs. Mechanistically, we discovered that miR-378a-5p played a protective role in AAA development by regulating actin-binding LIM protein 1 (ABLIM1)-megakaryoblastic leukemia 1 (MKL1) pathway. Conclusion: MiR-378a-5p exerts protective effects against AAA by maintaining VSMCs homeostasis via the ABLIM1-MKL1 pathway. Therefore, targeting miR-378a-5p may be an attractive therapeutic strategy for AAA treatment.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yaling Han

PROVIDER: PXD073033 | iProX | Tue Jan 13 00:00:00 GMT 2026

REPOSITORIES: iProX

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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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MiRNA-378a-5p attenuates the development of abdominal aortic aneurysm via ABLIM1-MKL1 signaling pathways

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