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Title:   Author  item
                                            GLADINE, CELINE - Institut National De La Recherche Agronomique (INRA)item
                                            Newman, Johnitem
                                            DURAND, THIERRY - National Council For Scientific Research-Cnrsitem
                                            Pedersen, Theresaitem
                                            GALANO, JEAN-MARIE - National Council For Scientific Research-Cnrsitem
                                            DEMOUGEOT, CELINE - University Of Franche-Comteitem
                                            BERDEAUX, OLIVIER - Universite De Bourgogneitem
                                            PUJOS-GUILLOT, ESTELLE - Institut National De La Recherche Agronomique (INRA)item
                                            MAZUR, ANDRZEJ - Institut National De La Recherche Agronomique (INRA)item
                                            COMTE, BLANDINE - Institut National De La Recherche Agronomique (INRA)
  Submitted to: PLOS ONE
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 12/30/2014
                                    Publication  Date: 11/13/2014
                                    Citation: Gladine, C., Newman, J.W., Durand, T., Pedersen, T.L., Galano, J., Demougeot, C., Berdeaux, O., Pujos-Guillot, E., Mazur, A., Comte, B. 2014. The omega-3 fatty acid DHA dose-dependently reduces atherosclerosis: a putative role for F4-neuroprostanes a specific class of peroxidized metabolites. PLoS One. 9(11):e111471.Interpretive Summary: Docosahexaenoic acid (DHA), a long chain n-3 PUFA common in the fats from cold water fish, is recognized for its cardioprotective effects slowing the progression of atherosclerosis. However, the chemical structure of this lipid makes it among the most susceptible to peroxidation in vivo, especially within the pro-oxidant environment of atherosclerotic plaque. Considering the paradox between DHA benefits and its susceptibility to peroxidation, we hypothesized that its peroxidized metabolites could contribute to the anti-atherogenic properties. The aim of the present study was to analyze the relations between DHA peroxidation and atherosclerosis development. Transgenic low density lipoprotein knock out mice(LDLR-/-; n=30/group) were fed for 20 weeks a diet enriched with animal fat (10%, w/w) and cholesterol (0.045%, w/w) in parallel with daily oral gavages (5 days/week) with either oleic acid rich oil (Control) or a mixture of oils providing 0.1, 1 or 2% of energy as DHA (Group-1, -2, and -3, respectively). Compared to Control, the highest dose of DHA reduced systolic blood pressure, plasma cholesterol, plasma triglycerides, and the extent of atherosclerotic plaques in a dose dependent manner.  An accumulation of DHA in liver and plasma (x2, p<0.001) of mice from the high dose Group was found to parallel an increased level of liver DHA peroxidation products and plasma DHA oxylipins. Together, these results show that DHA exerts atheroprotective effects despite the production of peroxidized molecules, and is consistent with other reports suggesting putative protective roles for long chain omega-3 fatty acid metabolites.
                                Technical Abstract: Objective. Consumption of long chain omega-3 polyunsaturated fatty acids is associated with reduced risks of cardiovascular disease but the role of their oxygenated metabolites remains unclear. We hypothesized that peroxidized metabolites of docosahexaenoic acid (DHA, 22:6 n-3) could play a role in atherosclerosis prevention. 

Methods and Results. LDLR-/- mice received an atherogenic diet and daily oral gavages with a mixture of oils providing 0%, 0.1%, 1% and 2% of energy as DHA for 20 weeks. Supplementation with DHA dose-dependently reduced atherosclerosis (R2=0.97), triglyceridemia (R2=0.97) and cholesterolemia (R2=0.96). Interestingly, targeted lipidomic analyses revealed that both the plasma and liver levels of n-3 polyunsaturated fatty acids and their corresponding oxygenated metabolites were substantially increased. Notably, the hepatic level of F4-neuroprostanes, specific peroxidation metabolites of DHA, was correlated with the hepatic DHA level (R2=0.99). Moreover, the unbiased statistical analysis revealed that hepatic level of F4-neuroprostanes was the variable the most negatively correlated with plaque extent and was one of just two predictive variables of atherosclerosis prevention.

Conclusion. Our study suggests that F4-neuroprostanes, a specific peroxidized product of DHA, is a putative contributor of the atherosclerosis prevention. Further investigations are needed to confirm this potential bioactivity and decipher the mechanisms of action.


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