Heme oxygenase (HO) isoforms degrade heme into carbon monoxide and bilirubin, and both affect renal function and attenuate vasoconstriction in the blood vessels. HO has two isoforms: HO-1 and HO-2. HO-1 is an inducible isoform, whereas HO-2 is a constitutive isoform. The arachidonic acid metabolites, such as epoxyeicosatrienoic acids (EETs), are cytochrome P450-derived eicosanoids that have many potent biological activities in the kidneys and vascular system. Although it is thought that HO and EET both might affect hypertension, the interaction between HO and EET pathways in the obesity that is often linked with hypertension in some patients is not well established. In this issue, Sodhi et al., studied the consequences of HO-2 knockout on EET production in the kidneys and whether EET agonist combined with soluble epoxide hydrolase (sEH, enzyme responsible for EET degradation) inhibitor affects the physiological parameters of HO-2 knockout mice. It was found that the HO-2 mice are obese, insulin-resistant, and hypertensive. In addition, the HO-2 knockout is associated with decreased CYP2c expression, decreased renal EET levels, increased HO-1 expression and activity, impairment of endothelial function in mouse aorta, and increased superoxide production. Finally, treatment of HO-2 knockout mice with a chemical agent, containing the activities of both EET agonist and sEH inhibition, increased renal and vascular EET levels, increased HO-1 expression, lowered blood pressure, reduced body weight and fat tissue, decreased serum TNF-α and MCP-1, increased adiponectin levels, and improved endothelial function in the aorta. Based on these results, the authors conclude that deficiencies in either the HO or EET system might contribute to the adverse effects and clinical progression of metabolic syndrome.
See article at J Pharmacol Exp Ther 2009, 331:906–916.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics