Does 20-Hydroxyeicosatetraenoic Acid Contribute to Sex Differences in Cardiovascular Risk by Increasing Oxidative Stress?

Abstract

Previous studies have indicated that there are large sex differences in the incidence of hypertension, and the role of androgens in enhancing the risk of cardiovascular disease is well recognized.1,2 However, the mechanisms by which androgens increase blood pressure are poorly understood. Recent studies have demonstrated that androgen-sensitive forms of hypertension are associated with increased production of 20-hydroxyeicosatetranoic acid (20-HETE) in the kidney and the vasculature.3 However, the role of 20-HETE in this form of hypertension has not been established, because this pathway has both prohypertensive and antihypertensive actions.4 At the level of the renal tubule, upregulation of the formation of 20-HETE inhibits sodium transport and opposes the development of hypertension, whereas in the vasculature, 20-HETE is a potent vasoconstrictor that promotes hypertension. The study of Singh et al5 in the current issue explores the role of 20-HETE in the development of endothelial dysfunction and hypertension in rats chronically treated with dihydrotestosterone. The results indicate that that the expression cytochrome P450 4A protein and the production of 20 HETE increase in renal arteries of rats treated with dihydrotestosterone. The increase in vascular 20-HETE production is because of upregulation of the expression of the cytochrome P450 4A8 isoform. The development of hypertension in these studies was associated with the development of endothelial dysfunction, as reflected by an impaired vasodilator response to acetylcholine, increased expression of the gp-91 …