Abstract BACKGROUND Thoracic aortic dissection (TAD) is a life-threatening vascular disease that requires effective drug treatment to prevent progression and rupture. Because arachidonic acid metabolism is involved in inflammation and vascular homeostasis, we investigated the roles of arachidonic acid metabolites in TAD pathogenesis and their utility as therapeutic targets. METHODS Serum metabolomics analysis was performed to characterize arachidonic acid metabolites in TAD patients and a TAD mouse model. 12/15-LOX expression was profiled in the aortic tissues of TAD patients and the TAD mouse model. Four-week-old male Alox15 knockout mice (Alox15 −/− ), 12-HETE-treated mice, ML351 (12/15-LOX inhibitor)-treated mice, and LY255283 (leukotriene B 4 receptor 2 [BLT2] antagonist)-treated mice received β-aminopropionitrile monofumarate (BAPN, 1 g/kg/day) for 4 weeks to model TAD, then underwent assessment of TAD progression. Interaction of 12-HETE produced by macrophages with BLT2 receptor-expressing cells was detected by molecular docking and immunoblotting. RESULTS Serum levels of 12-HETE and the expression of 12/15-LOX in aortic tissue were significantly increased in TAD patients and BAPN-treated TAD mice. BAPN-induced TAD progression was significantly ameliorated in Alox15-deficient or -suppressed mice. 12-HETE directly interacted with BLT2 receptors on macrophages, activating the downstream NOX-1/ROS/NF-κB signaling pathway to induce inflammatory cytokine release. This initiated inflammatory cell recruitment and exacerbated extracellular matrix degradation, leading to phenotype switching in vascular smooth muscle cells (VSMCs). Additionally, treatment with ML351 and LY255283 significantly reduced the rates of dissection rupture and combined treatment could maximize the curative effect. CONCLUSIONS 12-HETE may amplify the inflammatory cascade and trigger aberrant phenotype switching in VSMCs during TAD development. The reduction of circulating 12-HETE or antagonism of its receptor may be new targets for TAD prevention and treatment. Clinical Perspective What Is New? The expression levels of 12/15-LOX and its metabolite 12-HETE were elevated in TAD patients and TAD mice. Increased levels of 12-HETE directly bind to BLT2 receptors in macrophages, thereby initiating inflammatory cascades that downregulate VSMC differentiation markers through the suppression of IL-6. Deletion or pharmacologic inhibition of 12/15-LOX and suppression of BLT2 mitigated TAD development by alleviating inflammation and VSMC phenotype switching. What Are the Clinical Implications? The inhibition of 12-HETE-related pathways, through mechanisms such as reducing the plasma 12-HETE content or blocking its receptor, may represent a novel therapeutic strategy for TAD. Further studies are needed to explore the diagnostic value of serum 12-HETE as a novel biomarker for TAD.

A Vascular Dissection and Rupture Linked Metabolite Acts Via BLT2 Receptor