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<p>The <i>ORMDL3</i> (ORMDL sphingolipid biosynthesis regulator 3) gene has been genetically and functionally linked to inflammatory conditions and atherosclerosis (AS). The aim of this study is to elucidate the regulatory role of ORMDL3 in endothelial inflammation, lipid homeostasis, and apoptosis within the context of AS. A recombinant adeno-associated virus (rAAV) encoding the D377Y mutant of human proprotein convertase subtilisin/kexin type 9 (rAAV/D377Y-mPCSK9) was used to induce atherosclerosis in mice and to assess the role of ORMDL3 in atherogenesis and vascular inflammation. Mechanistic studies were conducted using human umbilical vein endothelial cells (HUVECs) to evaluate the effects of ORMDL3 on endothelial inflammation, lipid metabolism, and apoptotic signaling. ORMDL3 expression was found to be elevated in aortic atherosclerotic lesions and in HUVECs exposed to pro-atherogenic stimuli. Genetic deletion of <i>Ormdl3</i> in mice reduced plaque formation and vascular inflammation. In vitro, Ormdl3 knockdown suppressed the expression of adhesion molecules and proinflammatory cytokines, whereas its overexpression enhanced these responses, potentially through activation of the nuclear factor-kappa B (NF-κB) signaling pathway. <i>ORMDL3</i> deficiency attenuated lipid accumulation, endoplasmic reticulum (ER) stress, and apoptosis through upregulation of ABCA1. Lipidomic profiling indicated increased ceramide and dihydroceramide levels in ORMDL3-deficient cells. Pharmacological inhibition of ceramide biosynthesis partially reversed ABCA1 upregulation, suggesting a lipid-mediated regulatory mechanism. Additionally, miR-34a-5p binds directly to <i>ORMDL3</i> mRNA, downregulates its expression, and suppresses endothelial inflammation and apoptosis. Inflammatory stimulation led to downregulation of miR-34a-5p, indicating a feedback loop in <i>ORMDL3</i> regulation. ORMDL3 contributed to endothelial dysfunction and plaque instability by modulating ABCA1-mediated lipid efflux, ER stress, inflammation, and apoptotic pathways. The regulatory involvement of ceramide biosynthesis and the miR-34a-5p/ORMDL3 axis provides additional insight into the molecular mechanisms underlying ORMDL3-mediated atherogenesis. Therapeutic strategies targeting ORMDL3 may enhance endothelial function and promote plaque stabilization in patients with AS. </p><p><b>Trial Registration</b></p><p>Not applicable.</p>

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ORMDL3 as Key Regulator of Endothelial Dysfunction in Atherosclerosis via Sphingolipid Biosynthesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Liyuan Wang,
  • Yan Yun,
  • Yu Song,
  • Diming Zhao,
  • Jinzhang Li,
  • Shouji Zhang,
  • Zhengjun Wang,
  • Xiaochun Ma

摘要

The ORMDL3 (ORMDL sphingolipid biosynthesis regulator 3) gene has been genetically and functionally linked to inflammatory conditions and atherosclerosis (AS). The aim of this study is to elucidate the regulatory role of ORMDL3 in endothelial inflammation, lipid homeostasis, and apoptosis within the context of AS. A recombinant adeno-associated virus (rAAV) encoding the D377Y mutant of human proprotein convertase subtilisin/kexin type 9 (rAAV/D377Y-mPCSK9) was used to induce atherosclerosis in mice and to assess the role of ORMDL3 in atherogenesis and vascular inflammation. Mechanistic studies were conducted using human umbilical vein endothelial cells (HUVECs) to evaluate the effects of ORMDL3 on endothelial inflammation, lipid metabolism, and apoptotic signaling. ORMDL3 expression was found to be elevated in aortic atherosclerotic lesions and in HUVECs exposed to pro-atherogenic stimuli. Genetic deletion of Ormdl3 in mice reduced plaque formation and vascular inflammation. In vitro, Ormdl3 knockdown suppressed the expression of adhesion molecules and proinflammatory cytokines, whereas its overexpression enhanced these responses, potentially through activation of the nuclear factor-kappa B (NF-κB) signaling pathway. ORMDL3 deficiency attenuated lipid accumulation, endoplasmic reticulum (ER) stress, and apoptosis through upregulation of ABCA1. Lipidomic profiling indicated increased ceramide and dihydroceramide levels in ORMDL3-deficient cells. Pharmacological inhibition of ceramide biosynthesis partially reversed ABCA1 upregulation, suggesting a lipid-mediated regulatory mechanism. Additionally, miR-34a-5p binds directly to ORMDL3 mRNA, downregulates its expression, and suppresses endothelial inflammation and apoptosis. Inflammatory stimulation led to downregulation of miR-34a-5p, indicating a feedback loop in ORMDL3 regulation. ORMDL3 contributed to endothelial dysfunction and plaque instability by modulating ABCA1-mediated lipid efflux, ER stress, inflammation, and apoptotic pathways. The regulatory involvement of ceramide biosynthesis and the miR-34a-5p/ORMDL3 axis provides additional insight into the molecular mechanisms underlying ORMDL3-mediated atherogenesis. Therapeutic strategies targeting ORMDL3 may enhance endothelial function and promote plaque stabilization in patients with AS.

Trial Registration

Not applicable.