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

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Lipid Metabolism

Background:

• The ORMDL3 gene is linked to inflammatory diseases and atherosclerosis (AS).
• Understanding ORMDL3's role in endothelial cells is crucial for AS pathogenesis.
• Current knowledge gaps exist regarding ORMDL3's precise mechanisms in vascular inflammation and lipid homeostasis.

Purpose of the Study:

• To investigate the regulatory role of ORMDL3 in endothelial inflammation, lipid homeostasis, and apoptosis in the context of AS.
• To elucidate the molecular mechanisms by which ORMDL3 influences atherogenesis.
• To explore potential therapeutic targets related to ORMDL3 in AS.

Main Methods:

• Utilized a mouse model of atherosclerosis induced by rAAV/D377Y-mPCSK9.
• Conducted mechanistic studies in human umbilical vein endothelial cells (HUVECs).
• Assessed ORMDL3 expression, genetic deletion/knockdown/overexpression effects, NF-κB pathway activation, ABCA1 regulation, lipidomics, and miR-34a-5p interactions.

Main Results:

• ORMDL3 expression was elevated in atherosclerotic lesions and stimulated HUVECs.
• Ormdl3 deletion in mice reduced plaque formation and vascular inflammation.
• ORMDL3 modulated endothelial inflammation, lipid accumulation, ER stress, and apoptosis via ABCA1 and NF-κB pathways.
• miR-34a-5p directly targets ORMDL3, suppressing inflammation and apoptosis, with a feedback loop observed.

Conclusions:

• ORMDL3 exacerbates endothelial dysfunction and plaque instability in AS.
• ORMDL3 influences atherogenesis through ABCA1-mediated lipid efflux, ER stress, inflammation, and apoptosis.
• The miR-34a-5p/ORMDL3 axis and ceramide biosynthesis are key regulatory mechanisms in ORMDL3-mediated AS.
• Targeting ORMDL3 presents a potential therapeutic strategy for enhancing endothelial function and plaque stabilization in AS.