Docosahexaenoic Acid But Not Alpha-Linolenic Acid Ameliorates High Fat Diet Induced Atherosclerosis and Hypertension in APOE-/-Mice via Il-1 Mechanism

Current evidence from epidemiological studies, clinical trials and animal based research has shown an inverse relationship between omega3 fatty acids (n3FA) and cardiovascular events. Docosahexaenoic acid (DHA), a major n3FA in fish oil, has been studied in relation to inflammation but the exact molecular mechanisms involved remain unclear. Additionally, its role in atherosclerosis requires further elucidation. Plant derived dietary alpha Linolenic acid (ALA) has recently shown a favourable impact on hypertension in population based studies. The aim of this study was to determine whether there were significant differences in the effects of purified DHA and ALA on high blood pressure as a consequence of atheroma in mice fed high fat diet (HFD). Apolipoprotein E knockout mice (ApoE-/-) were fed a HFD alone (control) or HFD containing either DHA or ALA (100 mg per kg per day) for 12 weeks, and their blood pressure and atherosclerotic plaque development were assessed. There was no significant changes in the body weights among the three groups. However, the main systolic blood pressure fell by 40 mm Hg (p less 0.0001, n of 4), and diastolic blood pressure by 15mm Hg (p less 0.01, n of 4) in the group that received DHA than the control group, there was no significant changes in the group fed ALA. Furthermore, DHA fed mice had a significant increase in plasma HDLC to Total Cholesterol ratio (10.77 plus minus 1.85 vs.5.54 plus minus 1.07 in control group, p less 0.05, n of 10), without significant changes in LDLC and total Cholesterol levels. Interestingly, plasma cytokines MCP1, IL8 and RANTES were significantly decreased in the group received DHA compared to control (p less 0.01, n of 8 to 12). However, no significant impacts on plasma cytokines and lipid profiles were seen in the ALA fed group. ApoE-/- mice fed DHA showed significantly less atheroma in the distal vessels (Brachiocephalic arteries and descending part of aorta) than the apoE-/- mice on HFD alone or and ALA (p less 0.001, n of 12). Even though no significant changes were seen on plasma IL1a and IL1beta levels, there was a significant reduction in IL1b and IL1a proteins in the aortic sinuses of DHA fed animals (20 to 30 percent decreased, p less 0.01, n of 8) compared to controls. Moreover, there was a significant decrease in Mac3 (p less 0.01, n of 8) and TLR4 (p less 0.05, n of 6) positive areas of atherosclerotic plaque in the aortic roots of DHA than the control group. This is the first demonstration that DHA but not ALA has profound impacts on high blood pressure induced by HFD. We have previously shown that blocking of IL1 prevents the rise in blood pressure in response to HFD. Therefore, our study suggests that DHA modulates blood pressure by reducing inflammation in vessel walls through IL1 linked and HDLC dependent mechanism. These data raise the possibility of an entirely novel strategy to control atherosclerosis by diet modulation.(Authors abstract)