SLC1A5 prevents aortic aneurysm and dissection by glutaminolytic-epigenetic orchestration of vascular smooth muscle cell homeostasis

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. Aortic aneurysm and dissection are life-threatening vascular conditions with limited treatment options. Here, the authors identify the glutamine transporter SLC1A5 as a protective factor, demonstrating its role in maintaining vascular smooth muscle cell homeostasis by coupling glutamine metabolism to epigenetic regulation of contractile genes and STAT3-mediated inflammation. SLC1A5 overexpression attenuates disease progression in preclinical models.