Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase

Abstract

Abstract-In a randomized, double-blinded, controlled clinical trial, participants with peripheral arterial disease (75% hypertensive) consumed 30 g of milled flaxseed/d for 6 months. The flaxseed group exhibited significant reductions in systolic (−10 mm Hg) and diastolic (−7 mm Hg) blood pressure. Flaxseed contains the n3 fatty acid α-linolenic acid. Plasma α-linolenic acid increased with ingestion of flaxseed and was inversely associated with blood pressure. However, the antihypertensive mechanism was unclear. Oxylipins derived from polyunsaturated fatty acids regulate vascular tone. Therefore, the objective was to examine whether flaxseed consumption altered plasma oxylipins in a manner that influenced blood pressure. Plasma of FlaxPAD (Flaxseed for Peripheral Arterial Disease) participants underwent solid phase extraction and high-performance liquid chromatography-mass spectrometry/mass spectrometry analysis. The flaxseed group exhibited significant decreases in 8 plasma oxylipins versus control. Six of these (5,6-, 8,9-, 11,12-, 14,15-dihydroxyeicosatrienoic acid and 9,10-and 12,13-dihydroxyoctadecenoic acid) were products of soluble epoxide hydrolase, a pharmacological target for antihypertensive treatment. Patients exhibiting a decrease in total plasma soluble epoxide hydrolase-derived oxylipins, exhibited a significant decrease in systolic blood pressure (mean [ and infarction size 23 in animal models. The proposed relationship between epoxygenase-derived oxylipins and hypertension is depicted in Figure 1.95%To test the hypothesis that flaxseed decreased the levels of oxylipins associated with inflammation and vasoconstriction, the study objectives were 3-fold: (1) to characterize and quantify the plasma oxylipin profile of participants with PAD, (2) to compare changes in plasma oxylipin concentrations in the control and flaxseed groups, and (3) to determine the mechanism whereby any changes in oxylipins may have influenced blood pressure in the FlaxPAD Trial. Methods Participants and Food ProductsA randomized, double-blinded, parallel, controlled clinical trial was established to determine the cardiovascular effects of dietary flaxseed in patients with PAD.24 Seventy-five percent of the participants were diagnosed as hypertensive at baseline (blood pressure ≥140/90 mm Hg).2,24 Participants (n=110) consumed food products containing either 30 g of milled flaxseed (treatment) or a combination of mixed dietary oils, milled wheat, and bran (control) for 6 months. Further details of the food product composition, 25,26 participant enrollment, intervention allocation, clinical characteristics, and blood pressure outcomes have been previously published.2,24 The trial is available at http://www.clinicaltrials.gov/ct2/show/NCT00781950?term=grant+p ierce+flax&rank=1.All participants provided informed consent, and all procedures were performed according to institutional guidelines. The trial was approved by Health Canada and its Natural Health Product Directorate, the University of Manitoba Research Ethics Board,...

Dietary Flaxseed Reduces Central Aortic Blood Pressure Without Cardiac Involvement but Through Changes in Plasma Oxylipins

“…5 Finally, it was important to determine whether specific plasma oxylipins were associated with higher cBP. Dietary flaxseed decreased the concentration of proinflammatory and vasoconstricting oxylipins in the FlaxPAD Trial, 6 but their relationship to cBP is unknown.…”

“…Plasma oxylipins were analyzed by highperformance liquid chromatography mass spectrometry as previously described. 6 …”

“…The α-linolenic acid (ALA) content of flaxseed was identified as the bioactive component responsible for the antihypertensive action of dietary flaxseed. 5,6 ALA directly inhibited the enzymatic activity of soluble epoxide hydrolase, which reduced the concentrations of vasoconstrictive and proinflammatory oxylipins derived from soluble epoxide hydrolase in the plasma of the patients. 6 This previous work was done through conventional measurements of brachial blood pressure (BP) in patients.…”

“…5,6 ALA directly inhibited the enzymatic activity of soluble epoxide hydrolase, which reduced the concentrations of vasoconstrictive and proinflammatory oxylipins derived from soluble epoxide hydrolase in the plasma of the patients. 6 This previous work was done through conventional measurements of brachial blood pressure (BP) in patients. One of the aims of the present study was to investigate the capacity of flaxseed to influence central blood pressure (cBP).…”

Role of lipids and lipoproteins in myocardial biology and in the development of heart failure

“…Plasma α-linolenic acid (C18:3, n−3) increased with ingestion of flaxseed and was inversely associated with blood pressure. This effect may have been mediated via an inhibition of soluble epoxide hydrolase, which altered oxylipin concentrations [101]. 600…”