title: Epoxyeicosatrienoic acid agonist rescues the metabolic syndrome phenotype of HO-2-null mice.
abstract: Heme oxygenase (HO) and cytochrome P450 (P450)-derived epoxyeicosatrienoic acids (EETs) participate in vascular protection, and recent studies suggest these two systems are functionally linked. We examined the consequences of HO deficiency on P450-derived EETs with regard to body weight, adiposity, insulin resistance, blood pressure, and vascular function in HO-2-null mice. The HO-2-null mice were obese, displayed insulin resistance, and had high blood pressure. HO-2 deficiency was associated with decreases in cyp2c expression, EET levels, HO-1 expression, and HO activity and with an increase in superoxide production and an impairment in the relaxing response to acetylcholine. In addition, HO-2-null mice exhibited increases in serum levels of tumor necrosis factor (TNF)-alpha and macrophage chemoattractant protein (MCP)-1 and a decrease in serum adiponectin levels. Treatment of HO-2-null mice with a dual-activity EET agonist/soluble epoxide hydrolase inhibitor increased renal and vascular EET levels and HO-1 expression, lowered blood pressure, prevented body weight gain, increased insulin sensitivity, reduced subcutaneous and visceral fat, and decreased serum TNF-alpha and MCP-1, while increasing adiponectin and restoring the relaxing responses to acetylcholine. The decrease in cyp2c expression and EETs levels in HO-2-null mice underscores the importance of the HO system in the regulation of epoxygenase levels and suggests that protection against obesity-induced cardiovascular complications requires interplay between these two systems. A deficiency in one of these protective systems may contribute to the adverse manifestations associated with the clinical progression of the metabolic syndrome.
authors.affiliation: Department of Pharmacology New York Medical College, Valhalla, New York, USA.
authors.forename: Komal
authors.initials: K
authors.lastname: Sodhi
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Inoue
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Gotlinger
authors.forename: Martina
authors.initials: M
authors.lastname: Canestraro
authors.forename: Luca
authors.initials: L
authors.lastname: Vanella
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Vijay L
authors.initials: VL
authors.lastname: Manthati
authors.forename: Sreenivasulu Reddy
authors.initials: SR
authors.lastname: Koduru
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Michal L
authors.initials: ML
authors.lastname: Schwartzman
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000819:agonists / Q000031:analogs & derivatives* / Q000378:metabolism; D052242:Adiponectin / Q000096:biosynthesis / Q000097:blood; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D007672:Kidney Cortex / Q000201:enzymology / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis; D024821:Metabolic Syndrome / Q000201:enzymology* / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood; D014664:Vasodilation / Q000502:physiology
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C400322:cytochrome P-450 CYP2C subfamily; D013481:Superoxides; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C105245:heme oxygenase-2; D015126:8,11,14-Eicosatrienoic Acid