Abstract
Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with limited preventive pharmacotherapies based on angiotensin II receptor blockade. However, the underlying pathomechanisms of AAD are still unknown. Here, we find that glutamine transporters, particularly solute carrier family 1 member 5 (SLC1A5), in vascular smooth muscle cells (VSMCs) from both patients and mice with AAD are significantly downregulated. VSMC-specific Slc1a5 deficiency exacerbates experimental AAD formation, with a marked increase in VSMC phenotypic switch and inflammation. Mechanistically, SLC1A5 preserves contractile phenotype by facilitating glutamine metabolite acetyl-CoA production and subsequent histone H3 lysine 9 and 27 acetylation, and ameliorates inflammation by promoting acetylated STAT3 mitochondrial translocation, hence inhibiting its nuclear translocation. Intriguingly, enforced SLC1A5 expression in VSMCs in vivo largely alleviates experimental AAD. These findings reveal a metabolic link between SLC1A5-driven glutamine transport and vascular homeostasis, suggesting SLC1A5 may be a promising therapeutic target for AAD.
Data availability
The raw data of bulk RNA-seq data and CUT&Tag generated in this study has been deposited in the NCBI Gene Expression Omnibus (GEO) database under accession codes GSE309259 and GSE325132, respectively. The public expression profiling of aortic specimens from patients with aortic aneurysm is available in the NCBI GEO database under accession code GSE57691, and the Ang II-induced mouse aortic aneurysm and dissected aneurysm dataset is available in the NCBI GEO database under accession code GSE17901. The public single-cell RNA sequencing dataset used in this study is available in the NCBI GEO database under accession code GSE239620. All other relevant information about the data in this study is available from the corresponding author. Source data are provided in this paper.
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Acknowledgements
This work is supported by the National Natural Science Foundation of China (82270500 Z.L., 82574399 Z.L. and 82370444 S.X.) and the Guangdong Basic and Applied Basic Research Foundation (2026A1515012987 J.W. and 2024B1515020113 Z.L.).
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K.H., S.X., J.W., and Z.L. designed the study. P.Y. and Z.L. wrote the manuscript. P.Y. performed most of the in vitro and in vivo experiments. Z.G. and W.Y. performed the isolation and culture of MASMCs and replicated the molecular and histological experiments. C.Z. and Z.Z. participated in generating the murine models. Y.H. assessed the contractility of vascular smooth muscles using a wire myograph. Z.G. performed the bioinformatic analysis. P.Y. and Z.L. analyzed the data. M.S., Z.L., J.P., K.H., S.X., J.W., and Z.L. provided the reagents or materials, and critically reviewed and revised the manuscript. S.X., J.W., and Z.L. supervised the study and provided the funding. All the authors reviewed and approved the manuscript.
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Yang, P., Gao, Z., Ye, W. et al. SLC1A5 prevents aortic aneurysm and dissection by glutaminolytic-epigenetic orchestration of vascular smooth muscle cell homeostasis. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71856-4
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DOI: https://doi.org/10.1038/s41467-026-71856-4
