PT  - JOURNAL ARTICLE
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
TI  - Epoxyeicosatrienoic Acid Agonist Rescues the Metabolic Syndrome Phenotype of HO-2-Null Mice
AID  - 10.1124/jpet.109.157545
DP  - 2009 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 906--916
VI  - 331
IP  - 3
4099  - http://jpet.aspetjournals.org/content/331/3/906.short
4100  - http://jpet.aspetjournals.org/content/331/3/906.full
SO  - J Pharmacol Exp Ther2009 Dec 01; 331
AB  - 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