title: Anti-inflammatory effects of ω-3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin-II-dependent hypertension.
abstract: The mechanisms underlying the anti-inflammatory and antihypertensive effects of long-chain ω-3 polyunsaturated fatty acids (ω-3 PUFAs) are still unclear. The epoxides of an ω-6 fatty acid, arachidonic acid epoxyeicosatrienoic acids also exhibit antihypertensive and anti-inflammatory effects. Thus, we hypothesized that the major ω-3 PUFAs, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may lower the blood pressure and attenuate renal markers of inflammation through their epoxide metabolites. Here, we supplemented mice with an ω-3 rich diet for 3 weeks in a murine model of angiotensin-II-dependent hypertension. Also, because EPA and DHA epoxides are metabolized by soluble epoxide hydrolase (sEH), we tested the combination of an sEH inhibitor and the ω-3 rich diet. Our results show that ω-3 rich diet in combination with the sEH inhibitor lowered Ang-II, increased the blood pressure, further increased the renal levels of EPA and DHA epoxides, reduced renal markers of inflammation (ie, prostaglandins and MCP-1), downregulated an epithelial sodium channel, and upregulated angiotensin-converting enzyme-2 message and significantly modulated cyclooxygenase and lipoxygenase metabolic pathways. Overall, our findings suggest that epoxides of the ω-3 PUFAs contribute to lowering systolic blood pressure and attenuating inflammation in part by reduced prostaglandins and MCP-1 and by upregulation of angiotensin-converting enzyme-2 in angiotensin-II-dependent hypertension.
authors.affiliation: *Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA.
authors.forename: Arzu
authors.initials: A
authors.lastname: Ulu
authors.forename: Todd R
authors.initials: TR
authors.lastname: Harris
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Christina
authors.initials: C
authors.lastname: Miyabe
authors.forename: Hiromi
authors.initials: H
authors.lastname: Inoue
authors.forename: Gertrud
authors.initials: G
authors.lastname: Schuster
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Iosif
authors.forename: Jun-Yan
authors.initials: JY
authors.lastname: Liu
authors.forename: Robert H
authors.initials: RH
authors.lastname: Weiss
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000804:Angiotensin II; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000378:metabolism / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D062686:Epithelial Sodium Channel Blockers / Q000378:metabolism / Q000627:therapeutic use; D053503:Epithelial Sodium Channels / Q000737:chemistry / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism / Q000627:therapeutic use*; D006977:Hypertension, Renal / Q000178:diet therapy* / Q000188:drug therapy / Q000276:immunology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D012995:Solubility
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D015525:Fatty Acids, Omega-3; D018836:Inflammation Mediators; D000804:Angiotensin II; D004851:Epoxide Hydrolases; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2