title: 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.
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115-6110, USA; Elucida Research LLC, Beverly, MA 01915-0091, USA. Electronic address: rpmason@elucidaresearch.com.
authors.forename: R Preston
authors.initials: RP
authors.lastname: Mason
authors.affiliation: Elucida Research LLC, Beverly, MA 01915-0091, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Jacob
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Shrivastava
authors.affiliation: Elucida Research LLC, Beverly, MA 01915-0091, USA.
authors.forename: Samuel C R
authors.initials: SCR
authors.lastname: Sherratt
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
authors.forename: Amitabha
authors.initials: A
authors.lastname: Chattopadhyay
mesh_terms: D050197:Atherosclerosis / Q000188:drug therapy*; D002784:Cholesterol / Q000737:chemistry*; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D008560:Membrane Fluidity / Q000187:drug effects*
chemical_list: D008051:Lipid Bilayers; D004281:Docosahexaenoic Acids; D002784:Cholesterol; D015118:Eicosapentaenoic Acid
keywords: Cholesterol domain; Docosahexaenoic acid (DHA); Eicosapentaenoic acid (EPA); Membrane fluidity; Membrane structure