Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes

Abstract

Cholesterol crystalline domains characterize atherosclerotic membranes, altering vascular signaling and function. Omega-3 fatty acids reduce membrane lipid peroxidation and subsequent cholesterol domain formation. We evaluated non-peroxidation-mediated effects of eicosapentaenoic acid (EPA), other TG-lowering agents, docosahexaenoic acid (DHA), and other long-chain fatty acids on membrane fluidity, bilayer width, and cholesterol domain formation in model membranes. In membranes prepared at 1.5:1 cholesterol-to-phospholipid (C/P) mole ratio (creating pre-existing domains), EPA, glycyrrhizin, arachidonic acid, and alpha linolenic acid promoted the greatest reductions in cholesterol domains (by 65.5%, 54.9%, 46.8%, and 45.2%, respectively) compared to controls; other treatments had modest effects. EPA effects on cholesterol domain formation were dose-dependent. In membranes with 1:1 C/P (predisposing domain formation), DHA, but not EPA, dose-dependently increased membrane fluidity. DHA also induced cholesterol domain formation without affecting temperature-induced changes in-bilayer unit cell periodicity relative to controls (d-space; 57Å-55Å over 15-30°C). Together, these data suggest simultaneous formation of distinct cholesterol-rich ordered domains and cholesterol-poor disordered domains in the presence of DHA. By contrast, EPA had no effect on cholesterol domain formation and produced larger d-space values relative to controls (60Å-57Å; p<0.05) over the same temperature range, suggesting a more uniform maintenance of lipid dynamics despite the presence of cholesterol. These data indicate that EPA and DHA had different effects on membrane bilayer width, membrane fluidity, and cholesterol crystalline domain formation; suggesting omega-3 fatty acids with differing chain length or unsaturation may differentially influence membrane lipid dynamics and structural organization as a result of distinct phospholipid/sterol interactions.

The eicosapentaenoic acid:arachidonic acid ratio and its clinical utility in cardiovascular disease

“…Membrane models have suggested that EPA and DHA have different molecular locations and orientations resulting in distinct membrane structures which may confer different biological activities [70]. Differences in membrane interactions between EPA and DHA may result in the inhibition of cholesterol crystalline domains by EPA but not DHA, which may impact endothelial function [71]. Furthermore, EPA is more efficiently incorporated into HDL particles than DHA which prolongs and increases EPA's ability to inhibit HDL oxidation compared with DHA [72].…”

<p>Spotlight on Icosapent Ethyl for Cardiovascular Risk Reduction: Evidence to Date</p>

“…29,30 When incorporated into cell membranes, EPA confers membrane stability even in the setting of increased cholesterol load, which in turn imparts a protective effect against endothelial dysfunction. 31 Moreover, higher concentration of EPA found in atherosclerotic plaques has been shown to be associated with less foam cells and a decrease in the expression of matrix metalloproteinases, which are thought to increase plaque stability. 32 EPA Effects on Cardiovascular Outcomes (Table 2) The first cardiovascular outcomes trial on EPA was the Japan EPA Lipid Intervention Study (JELIS) study published in 2007.…”

Aneurysmal Subarachnoid Hemorrhage and Resolution of Inflammation

“…Additionally, recent mechanistic studies have shown that minor changes in the EPA content of endothelial membranes may markedly alter the biophysical properties of the membrane [28]. Furthermore, changes in membrane fluidity, thickness, and deformability induced by modifications to lipid dynamics and/or structural organization can profoundly impact endothelial function [29].…”

“…Although the role of DHA neurolipidomics in neurovascular coupling appears to be underestimated, substantial experimental evidence suggests that the morphologic and functional integrity of the neurovascular unit largely depends on high DHA enrichment [37,40,43]. Moreover, the potential role of EPA in microvascular function further supports the evolutionary importance of these essential nutrients to maintain efficient functional couplings between neural and vascular networks [28,29]. A functional neurovascular unit may be crucial not only for neurovascular coupling but also for BBB integrity and neurogenesis.…”