Stress-induced vascular remodeling: novel insight into the role of omega-3 fatty acid metabolite, 4-oxoDHA

Abstract Background Stress has garnered significant attention as a prominent risk factor for inflammation-related diseases, particularly cardiovascular diseases (CVDs). However, the precise mechanisms underlying stress-driven CVDs remain elusive, thereby impeding the development of effective preventive and therapeutic strategies. Methods To explore the correlation between plasma lipid metabolites and depressive states, we conducted a study involving healthy volunteers (n=408). Liquid chromatography (LC)/mass spectrometry (MS)/MS-based lipidomics and the self-rating depression (SDS) scale questionnaire were employed for data collection. In addition, we utilized a mouse model by subjecting mice to restraint stress and investigating the impact of stress on plasma lipid metabolites and vascular remodeling following carotid ligation. In vitro functional and mechanistic studies were performed using macrophages, endothelial cells, and neutrophil cells. Results Our findings revealed a significant association between depressive state and reduced plasma levels of 4-oxoDHA, a specific omega-3 fatty acid metabolite regulated by 5-lipoxygenase (LO) in neutrophils in healthy volunteers. In mice, restraint stress led to decreased plasma 4-oxoDHA levels and exacerbated vascular remodeling. Moreover, 4-oxoDHA demonstrated the ability to enhance Nrf2-HO-1 pathways, exerting anti-inflammatory effects on endothelial cells and macrophages. Mechanistically, stress-induced noradrenaline triggered the degradation of 5-LO in neutrophils through the proteasome system, facilitated by dopamine D2-like receptor activation. The reduction in circulating 4-oxoDHA resulted in the downregulation of the Nrf2-HO-1 anti-inflammatory axis and an increase in ICAM-1 expression, vascular permeability, and remodeling. Conclusions Our study unveiled a novel stress-induced pathway of vascular inflammation, mediated through the regulation of omega-3 fatty acid metabolites. Reduced levels of circulating 4-oxoDHA under stress conditions may serve as a promising biomarker for stress. This understanding of the interplay between neurobiology and lipid metabolism provides a potential avenue for the development of treatments aimed at preventing stress-induced systemic neuroinflammation. Highlights – Our study reveals that stress-induced reduction in circulating levels of a specific omega-3 fatty acid metabolite, 4-oxoDHA, contributes to vascular inflammation. – We have identified a novel pathway that explains how stress promotes systemic vascular inflammation by regulating omega-3 fatty acid metabolites in the circulation. – Our findings provide new evidence for the role of 4-oxoDHA in maintaining Nrf2-ARE-related anti-inflammatory functions in endothelial cells and macrophages.