20-HETE and Blood Pressure Regulation

Abstract

20-Hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE) is a cytochrome P450 (CYP)–derived omega-hydroxylation metabolite of arachidonic acid. 20-HETE has been shown to play a complex role in blood pressure regulation. In the kidney tubules, 20-HETE inhibits sodium reabsorption and promotes natriuresis, thus, contributing to antihypertensive mechanisms. In contrast, in the microvasculature, 20-HETE has been shown to play a pressor role by sensitizing smooth muscle cells to constrictor stimuli and increasing myogenic tone, and by acting on the endothelium to further promote endothelial dysfunction and endothelial activation. In addition, 20-HETE induces endothelial angiotensin-converting enzyme, thus, setting forth a potential feed forward prohypertensive mechanism by stimulating the renin–angiotensin–aldosterone system. With the advancement of gene sequencing technology, numerous polymorphisms in the regulatory coding and noncoding regions of 20-HETE–producing enzymes, CYP4A11 and CYP4F2, have been associated with hypertension. This in-depth review article discusses the biosynthesis and function of 20-HETE in the cardiovascular system, the pharmacological agents that affect 20-HETE action, and polymorphisms of CYP enzymes that produce 20-HETE and are associated with systemic hypertension in humans.

Kidney Cadmium Toxicity, Diabetes and High Blood Pressure: The Perfect Storm

“…In the thick ascending limb of the loop of Henle (TALH), 20-HETE has a natriuretic effect because it inhibits Na + -K + -2Cl − and 70pS K + transport, causing a reduction in reabsorption of sodium (Fan et al 2015). In vascular smooth muscle cells, 20-HETE is a local vasoconstrictor and thus is pro-hyper-tensive (Wu et al 2014a). Role for 20-HETE in pathogenesis of hypertension can be deduced from studies, detailed below.…”

“…The enzymes of the cytochrome P450 (CYP) superfamily, especially of the CYP4 family (CYP4A11 and CYP4F2) in human kidneys have also been linked to the role of the kidneys in systemic blood pressure regulation (Satarug et al 2006;Fan et al 2015). The CYP4A11 and CYP4F2 enzymes catalyse ɷ-hydroxylation of the arachidonic acid (Lasker et al 2000) to produce 20-hydroxyeicosatetraenoic acid (20-HETE), involved in regulation of salt balance in the kidney (Wu et al 2014a;Fan et al 2015). CYP4F2 and CYP4F3B also catalyze the inactivation of leukotriene B4, a potent inflammatory agent, suggesting their role in tissue inflammation (Johnson et al 2015).…”

The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monooxygenase Complexed with Octane Discloses Several Structural Adaptations for ω-Hydroxylation

“…skin. Additionally, some cytochrome P450 -hydroxylases, such as human cytochrome P450s 4A11, 4F2, and 4F3b, catalyze the formation of 20-hydroxyeicosatetraenoic acid from arachidonic acid, which contributes to regulation of vascular tone and renal sodium absorption (10,11). Genetic association studies link variants of human CYP4A11 and CYP4F2 with increased risks for hypertension, which in the case of CYP4A11 is likely to reflect dysregulation of renal sodium uptake as the blood pressure increase is sensitive to levels of dietary salt (12,13).…”

Hypertension Is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid–Mediated Kidney Injury in Diabetic Nephropathy

“…In the renal vasculature, 20-HETE increases BP via inactivation of the smooth muscle calcium-sensitive potassium channel, causes vasoconstriction of the renal microvasculature, potentiates the effects of vasoconstrictors, and enhances endothelial angiotensinconverting enzyme (ACE) expression leading to increased systolic BP. 10,11 By contrast, 20-HETE can reduce BP by promoting natriuresis via inhibition of the Na + -K + -ATPase in the proximal tubules and the Na + -K + -2Cl 2 cotransporter in the thick ascending limb of the loop of Henle. [12][13][14] In addition to the renal tubules and vasculature, glomeruli also produce 20-HETE, which can either protect the kidney from injurymediated albuminuria or contribute to injury by promoting high glucose-mediated podocyte apoptosis or tubular hypertrophy.…”