Abstract
Thoracic aortic dissection (TAD), a life-threatening vascular emergency requiring urgent pharmacological intervention, prompted investigation into arachidonic acid metabolites based on their established roles in inflammation and vascular homeostasis. Through comprehensive plasma metabolomics analysis performed in both TAD patients and a β-aminopropionitrile monofumarate (BAPN)-induced mouse model, significant elevation of 12-hydroxyeicosatetraenoic acid (12-HETE) was identified, accompanied by marked upregulation of its synthetic enzyme 12/15-lipoxygenase (12/15-LOX) in dissected aortic tissues. The pathogenetic significance was further demonstrated by the substantial protection against TAD progression that was observed in Alox15-deficient mice. Mechanistically, 12-HETE was confirmed to function as an endogenous ligand for the BLT2 receptor on macrophages, leading to activation of the NOX-1/ROS/NF-κB signaling cascade. This signaling activation was shown to induce inflammatory cytokine release and promote inflammatory cell recruitment, ultimately resulting in pathological phenotype switching of vascular smooth muscle cells. The therapeutic potential was validated by significant reduction in dissection rupture rates that was achieved with either the 12/15-LOX inhibitor ML351 or the BLT2 antagonist LY255283, with maximal efficacy being demonstrated when both agents were administered in combination. These findings establish the 12-HETE-BLT2 axis as a key driver of TAD pathogenesis and validate its potential as a promising therapeutic target for clinical intervention.