20-HETE and Hypertension

Abstract

Previous studies established that arachidonic acid is metabolized by the cytochrome P450 (CYP) enzymes of the 4A and 4F families to 20-hydroxyeicosatetraenoic (20-HETE) that regulates renal function and vascular tone. Elevations in the 20-HETE have been reported to increase blood pressure by promoting endothelial dysfunction, vascular inflammation, oxidative stress and endothelial expression of angiotensin-converting enzyme, which increase circulating angiotensin II levels. However, mutations in CYP4F2 and CYP4A11 that inhibit the formation of 20-HETE have been linked to hypertension in human genetic studies, and a deficiency in 20-HETE promotes sodium retention and hypertension in Dahl salt-sensitive rats. This Perspective focuses on knowledge gaps concerning the pro- versus anti-hypertensive actions of 20-HETE and the GPR75/20-HETE receptor in mediating these effects.

Keywords: blood pressure; cytochrome P450 CYP4A; hypertension; kidney; mutation.

Figure 1.. Role of 20-HETE in models of hypertension.

Renal and vascular production of 20-HETE are altered in human genetic studies, experimental models of hypertension and CYP4A, and CYP4F transgenic and knockout (KO) mouse models. Elevations in the vascular formation of 20-HETE increase renal and peripheral vascular resistance and produce salt-insensitive forms of hypertension, whereas decreases in the formation of 20-HETE promote salt-sensitive hypertension. DHT-dihydrotestosterone, ET1-endothelin 1, ANG II-angiotensin II, LNAME, N(v)-nitro-L-arginine methyl ester.