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<p>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 <i>Slc1a5</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月15日

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  • Pinglian Yang,
  • Zhechang Gao,
  • Weile Ye,
  • Chunhong Zhou,
  • Zhihua Zheng,
  • Meiming Su,
  • Yu He,
  • Zhuoming Li,
  • Jaroslav Pelisek,
  • Ke He,
  • Suowen Xu,
  • Jiaojiao Wang,
  • Zhiping Liu

摘要

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.