Abstract-We have shown previously that increased vascular endothelial expression of CYP4A2 leads to 20-hydroxyeicosatetraenoic (20-HETE)-dependent hypertension. The renin-angiotensin system is a key regulator of blood pressure.In this study, we examined possible interactions between 20-HETE and the renin-angiotensin system. In normotensive (110Ϯ3 mm Hg) Sprague-Dawley rats transduced with a lentivirus expressing the CYP4A2 cDNA under the control of an endothelial-specific promoter (VECAD-4A2), systolic blood pressure increased rapidly, reaching 139Ϯ1, 145Ϯ3, and 150Ϯ2 mm Hg at 3, 5, and 10 days after transduction; blood pressure remained elevated, thereafter, with maximum levels of 163Ϯ3 mm Hg. Treatment with lisinopril, losartan, or the 20-HETE antagonist 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid decreased blood pressure to control values, but blood pressure returned to its high levels after cessation of treatment. Endothelial-specific overexpression of CYP4A2 resulted in increased expression of vascular angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor and increased levels of plasma and tissue angiotensin II; all were attenuated by treatment with HET0016, an inhibitor of 20-HETE synthesis, or with 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid. In cultured endothelial cells, 20-HETE specifically and potently induced ACE expression without altering the expression of ACE2, angiotensinogen, or angiotensin II receptors. This is the first study to demonstrate that 20-HETE, a key constrictor eicosanoid in the microcirculation, induces ACE and angiotensin II type 1 receptor expression and increases angiotensin II levels, suggesting that the mechanisms by which 20-HETE promotes hypertension include activation of the renin-angiotensin system that is likely initiated at the level of ACE induction. It is endowed with unique biological activities relevant to the regulation of vascular tone, renal function, and blood pressure. The involvement of 20-HETE in hypertension has been significantly documented in animal models and humans. 20-HETE is a vasoconstrictor and natriuretic eicosanoid; hence, its contribution to the regulation of blood pressure depends on its sites of synthesis and action. In the vasculature, 20-HETE enhances the responsiveness to constrictor stimuli, including pressure, oxygen, phenylephrine, and endothelin 1, as well as inhibition of NO synthesis by mechanisms that include production of constrictor eicosanoids, inhibition of the smooth muscle cell large conductance Ca 2ϩ -activated K ϩ channel, and the sensitization of the contractile apparatus to [Ca 2ϩ ] through phosphorylation of MLC20. 1 We and others 2-4 demonstrated that, in circulatory districts other than the pulmonary, 20-HETE reduces endothelial-dependent vasorelaxation by uncoupling endothelial NO synthase. 5,6 In the kidney, 20-HETE biosynthesis is prominent in the proximal tubule and thick ascending limb. It promotes natriuresis by inhibiting Na ϩ /K ϩ -ATPase activity in the proximal tubule and inhibiting the Na ϩ -K ϩ -...
17(R),18(S)-Epoxyeicosatetraenoic acid [17(R),18(S)-EETeTr], a cytochrome P450 epoxygenase metabolite of eicosapentaenoic acid (EPA), exerts negative chronotropic effects and protects neonatal rat cardiomyocytes against Ca2+-overload with an EC50 ~1–2 nM. Structure-activity studies revealed a cis-Δ11,12- or Δ14,15-olefin and a 17(R),18(S)-epoxide are minimal structural elements for anti-arrhythmic activity whereas antagonist activity was often associated with the combination of a Δ14,15-olefin and a 17(S),18(R)-epoxide. Compared with natural material, the agonist and antagonist analogs are chemically and metabolically more robust and several show promise as templates for future development of clinical candidates.
High dietary potassium stimulates the renal expression of cytochrome P450 (CYP) epoxygenase 2C23, which metabolizes arachidonic acid (AA). Because the AA metabolite 11,12-epoxyeicosatrienoic acid (11, can inhibit the epithelial sodium channel (ENaC) in the cortical collecting duct, we tested whether dietary potassium modulates ENaC function. High dietary potassium increased 11,12-EET in the isolated cortical collecting duct, an effect mimicked by inhibiting the angiotensin II type I receptor with valsartan. In patch-clamp experiments, a high potassium intake or treatment with valsartan enhanced AA-induced inhibition of ENaC, an effect mediated by a CYP-epoxygenase-dependent pathway. Moreover, high dietary potassium and valsartan each augmented the inhibitory effect of 11,12-EET on ENaC. Liquid chromatography/mass spectrometry showed that the rate of EET conversion to dihydroxyeicosatrienoic acids (DHET) was lower in renal tissue obtained from rats on a high-potassium diet than from those on a control diet, but this was not a result of altered expression of soluble epoxide hydrolase (sEH). Instead, suppression of sEH activity seemed to be responsible for the 11,12-EET-mediated enhanced inhibition of ENaC in animals on a high-potassium diet. Patch-clamp experiments demonstrated that 11,12-DHET was a weak inhibitor of ENaC compared with 11,12-EET, whereas 8,9-and 14,15-DHET were not. Furthermore, inhibition of sEH enhanced the 11,12-EET-induced inhibition of ENaC similar to high dietary potassium. In conclusion, high dietary potassium enhances the inhibitory effect of AA and 11,12-EET on ENaC by increasing CYP epoxygenase activity and decreasing sEH activity, respectively. 21: 166721: -167721: , 201021: . doi: 10.1681 We previously demonstrated that cytochrome P450 (CYP) epoxygenase-dependent arachidonic acid (AA) metabolism inhibited epithelial sodium channel (ENaC) in the cortical collecting duct (CCD) and that 11,12-epoxyeicosatrienoic acid (11,12-EET) was responsible for mediating the effect of AA on ENaC. 1 Furthermore, the observation that AA failed to inhibit ENaC in the CCD of the mice with a low expression of CYP2C44 suggests that CYP2C44 and its orthologs may be responsible for mediating the inhibitory effect of AA. 2 The expression of CYP2C44 or its orthologs has been shown to be regulated by dietary Na intake: A high Na intake stimulates 2 whereas a low Na intake suppresses the expression of CYP2C44 homologue. 3 A large body of evidence has suggested that EET plays a role in the regulation of renal Na transport and salt-sensitive hypertension. 1,2,4,5 Inhibition of CYP epoxygenase-dependent AA metabolism results in the development of salt-sensitive hypertension 5,6 ; however, the BP returned to normal after the removal of the epoxygenase inhibitor, even when the animals were still kept on a high-Na diet. The high Na intake-induced in- J Am Soc Nephrol
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.