TY - JOUR T1 - Epoxyeicosatrienoic Acid Agonist Rescues the Metabolic Syndrome Phenotype of HO-2-Null Mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 906 LP - 916 DO - 10.1124/jpet.109.157545 VL - 331 IS - 3 AU - Komal Sodhi AU - Kazuyoshi Inoue AU - Katherine H. Gotlinger AU - Martina Canestraro AU - Luca Vanella AU - Dong Hyun Kim AU - Vijay L. Manthati AU - Sreenivasulu Reddy Koduru AU - John R. Falck AU - Michal L. Schwartzman AU - Nader G. Abraham Y1 - 2009/12/01 UR - http://jpet.aspetjournals.org/content/331/3/906.abstract N2 - 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)-α 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-α 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.© 2009 by The American Society for Pharmacology and Experimental Therapeutics ER -