Epoxyeicosatrienoic acid agonist rescues the metabolic syndrome phenotype of HO-2-null mice

Komal Sodhi, Kazuyoshi Inoue, Katherine H. Gotlinger, Martina Canestraro, Luca Vanella, Dong Hyun Kim, Vijay L. Manthati, Sreenivasulu Reddy Koduru, J R Falck, Michal L. Schwartzman, Nader G. Abraham

Research output: Contribution to journalArticle

103 Scopus citations

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)-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.

Original languageEnglish (US)
Pages (from-to)906-916
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume331
Issue number3
DOIs
StatePublished - Dec 1 2009

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Sodhi, K., Inoue, K., Gotlinger, K. H., Canestraro, M., Vanella, L., Kim, D. H., Manthati, V. L., Koduru, S. R., Falck, J. R., Schwartzman, M. L., & Abraham, N. G. (2009). Epoxyeicosatrienoic acid agonist rescues the metabolic syndrome phenotype of HO-2-null mice. Journal of Pharmacology and Experimental Therapeutics, 331(3), 906-916. https://doi.org/10.1124/jpet.109.157545