Abstract
Treatment with high dose icosapent ethyl (IPE), an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA), significantly reduced ischemic events in patients with either cardiovascular disease (CV) or diabetes plus other risk factors (REDUCE-IT) but the mechanism is not well understood. We compared the effects of EPA, docosahexaenoic acid (DHA), and the omega-6 fatty acid arachidonic acid (AA) on bioavailability of nitric oxide (NO) and fatty acid composition. Human umbilical vein endothelial cells (HUVECs) were pretreated with EPA, DHA, or AA (10 µM). Cells were stimulated with calcium ionophore and NO and peroxynitrite (ONOO−) were measured using porphyrinic nanosensors. Levels of EPA, DHA, AA and other fatty acids were measured by gas chromatography (GC). EPA treatment caused the greatest NO release (18%, p < 0.001) and reduction in ONOO− (13%, p < 0.05) compared to control; the [NO]/[ ONOO−] ratio increased by 35% (p < 0.001). DHA treatment increased NO levels by 12% (p < 0.01) but had no effect on ONOO− release. AA did not affect either NO or ONOO− release. Fatty acid treatments increased their respective levels in endothelial cells. EPA levels increased 10-fold to 4.59 mg/g protein (p < 0.001) with EPA treatment and the EPA/AA ratio increased by 10-fold (p < 0.001) compared to vehicle. Only EPA increased docosapentaenoic acid (DPA, omega-3) levels by 2-fold (p < 0.001). AA alone decreased the EPA/AA ratio 4-fold (p<0.001). These findings support a preferential benefit of EPA on endothelial function and omega-3 fatty acid content.
Highlights
Endothelial cells mediate vasodilation through the regulated release of nitric oxide (NO) in response to changes in blood flow and various pharmacologic interventions [1,2,3,4,5]
eicosapentaenoic acid (EPA) caused a significant increase in NO release compared to control (18%, 590 ± 10 versus 501 ± 14 nM, p < 0.001), compared to docosahexaenoic acid (DHA) (6%, 590 ± 10 versus 559 ± 8 nM, p < 0.05), and compared to arachidonic acid (AA) (11%, 590 ± 10 versus 533 ± 9 nM, p < 0.001)
AA failed to cause a significant increase in NO release compared to control
Summary
Endothelial cells mediate vasodilation through the regulated release of nitric oxide (NO) in response to changes in blood flow and various pharmacologic interventions [1,2,3,4,5]. Beyond its effects on smooth muscle cell relaxation, NO regulates platelet and leukocyte adherence, hemos tasis/thrombosis and fibrinolysis [6, 7]. In a highly coordinated fashion, endothelial cells produces potent vasoconstrictors, including endothelin-1, angiotensin II, thromboxane A2 (TXA2), and prostaglandin H2. NO is generated by three distinct dimeric nitric oxide synthase (NOS) enzymes that catalyze the oxidation of L-arginine into L-citrulline and NO. Many cell types express constitutively two of these enzymes, endothelial NOS (eNOS) and neuronal NOS (nNOS). Inducible NOS (iNOS) is transcriptionally regulated in response to inflammatory stimuli. NO is a major scavenger of O2− that generates the powerful oxidant peroxynitrite (ONOO− ) by a rapid, diffusion limited reaction [12, 13]
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