12-Hydroxyeicosapentaenoic acid inhibits foam cell formation and ameliorates high-fat diet-induced pathology of atherosclerosis in mice

Atherosclerosis is a chronic inflammatory disease associated with macrophage aggregate and transformation into foam cells. In this study, we sought to investigate the impact of dietary intake of omega 3 fatty acid on the development of atherosclerosis, and demonstrate the mechanism of action by identifying anti-inflammatory lipid metabolite. Mice were exposed to a high-fat diet (HFD) supplemented with either conventional soybean oil or alpha -linolenic acid-rich linseed oil. We found that as mice became obese they also showed increased pulsatility and resistive indexes in the common carotid artery. In sharp contrast, the addition of linseed oil to the HFD improved pulsatility and resistive indexes without affecting weight gain. Histological analysis revealed that dietary linseed oil inhibited foam cell formation in the aortic valve. Lipidomic analysis demonstrated a particularly marked increase in the eicosapentaenoic acid-derived metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) in the serum from mice fed with linseed oil. When we gave 12-HEPE to mice with HFD, the pulsatility and resistive indexes was improved. Indeed, 12-HEPE inhibited the foamy transformation of macrophages in a peroxisome proliferator-activated receptor (PPAR)gamma -dependent manner. These results demonstrate that the 12-HEPE-PPAR gamma axis ameliorates the pathogenesis of atherosclerosis by inhibiting foam cell formation.

Automated summary

This study investigated the impact of dietary intake of omega-3 fatty acids on atherosclerosis development and found that supplementing high-fat diet with alpha-linolenic acid-rich linseed oil improved atherosclerosis while inhibiting foam cell formation. The study also revealed a significant increase in the anti-inflammatory metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) in mice fed with linseed oil, which improved pulsatility and resistive indexes and inhibited macrophage foam cell transformation in a PPARγ-dependent manner.