Authors
Lu-Zhe Huang, Li-Li Chen, Jian-Jun Wang, Xi-Guan Du, Xiong-Ying Zhang, Fang-Wei Zhan, Jun-Xing Zhu
Published in
Naunyn-Schmiedeberg's archives of pharmacology. Jul 07, 2026. Epub Jul 07, 2026.
Abstract
Abdominal aortic aneurysm (AAA) is a degenerative vascular disease with a potentially fatal risk, and effective pharmacological therapies are still lacking. γ-Aminobutyric acid (GABA) is a naturally occurring four-carbon non-protein amino acid found in vegetables and fruits and has traditionally been used for the treatment of central nervous system disorders. Due to its antihypertensive and immunomodulatory properties, the potential therapeutic value of GABA in cardiovascular diseases has attracted increasing attention. However, the mechanism by which GABA exerts its effects in AAA remains unclear. First, network pharmacology was employed to obtain the molecular structure of GABA and to identify GABA-related targets and AAA-associated targets. The overlapping targets were then used to construct and analyze a protein-protein interaction (PPI) network, followed by Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Finally, an AAA rat model was established to validate the findings in vivo. A total of 202 potential targets of GABA and 5,950 AAA-associated targets were identified, among which 111 were overlapping targets. PPI network analysis indicated that AKT1 was the most important target of GABA in the treatment of AAA. KEGG analysis showed that the PI3K/AKT signaling pathway was the key pathway through which GABA exerted its therapeutic effects. GO analysis demonstrated that GABA exerted its pharmacological effects mainly through multiple mechanisms, including the regulation of extracellular matrix(ECM) degradation, amino acid metabolism, and apoptosis.In vivo experiments confirmed that GABA significantly inhibited the phosphorylation levels of PI3K and AKT1 in the aneurysmal aortic wall tissues of rats without affecting the total protein expression levels of PI3K and AKT1. In addition, GABA reduced the expression and activity of MMP2 and MMP9, thereby effectively inhibiting ECM degradation and delaying the progression of AAA. However, GABA no longer exerted additional effects after PI3K inhibition. Notably, bicuculline, a specific inhibitor of the GABA-A receptor, significantly reversed the therapeutic effects of GABA. GABA may regulate the PI3K/AKT signaling pathway through the GABA-A receptor, reducing ECM degradation and thus delaying the progression of AAA.
PMID:
42410225
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.
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