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20-HETE and blood pressure regulation: clinical implications.

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.

SUBMITTER: Wu CC

PROVIDER: S-EPMC4292790 | biostudies-literature | 2014 Jan-Feb

REPOSITORIES: biostudies-literature

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20-HETE and blood pressure regulation: clinical implications.

Wu Cheng-Chia CC Gupta Tanush T Garcia Victor V Ding Yan Y Schwartzman Michal L ML

Cardiology in review 20140101 1

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 an ...[more]

PMID: 23584425

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Project description:20-HETE is a potent vasoconstrictor that is implicated in the regulation of blood pressure, cerebral blood flow and neuronal death following ischemia. Numerous human genetic studies have shown that inactivating variants in the cytochrome P450 enzymes that produce 20-HETE are associated with hypertension, stroke and cerebrovascular disease. However, little is known about the expression and cellular distribution of the cytochrome P450A enzymes (CYP4A) that produce 20-HETE or the newly discovered 20-HETE receptor (GPR75) in the brain. The present study examined the cell types and regions in the rat forebrain that express CYP4A and GPR75. Brain tissue slices from Sprague Dawley (SD), Dahl Salt-Sensitive (SS) and CYP4A1 transgenic rat strains, as well as cultured human cerebral pericytes and cerebral vascular smooth muscle cells, were analyzed by fluorescent immunostaining. Tissue homogenates from these strains and cultured cells were examined by Western blot. In the cerebral vasculature, CYP4A and GPR75 were expressed in endothelial cells, vascular smooth muscle cells and the glial limiting membrane of pial arteries and penetrating arterioles but not in the endothelium of capillaries. CYP4A, but not GPR75, was expressed in astrocytes. CYP4A and GPR75 were both expressed in a subpopulation of pericytes on capillaries. The diameters of capillaries were significantly decreased at the sites of first and second-order pericytes that expressed CYP4A. Capillary diameters were unaffected at the sites of other pericytes that did not express CYP4A. These findings implicate 20-HETE as a paracrine mediator in various components of the neurovascular unit and are consistent with 20-HETE's emerging role in the regulation of cerebral blood flow, blood-brain barrier integrity, the pathogenesis of stroke and the vascular contributions to cognitive impairment and dementia. Moreover, this study highlights GPR75 as a potential therapeutic target for the treatment of these devastating conditions.

Project description:BackgroundAbnormal blood pressure (BP) responses to exercise can predict adverse cardiovascular outcomes, but their optimal measurement and definitions are poorly understood. We combined frequently sampled BP during cardiopulmonary exercise testing with vascular stiffness assessment to parse cardiac and vascular components of exercise BP.MethodsCardiopulmonary exercise testing with BP measured every two minutes and resting vascular tonometry were performed in 2858 Framingham Heart Study participants. Linear regression was used to analyze sex-specific exercise BP patterns as a function of arterial stiffness (carotid-femoral pulse wave velocity) and cardiac-peripheral performance (defined by peak O2 pulse).ResultsOur sample was balanced by sex (52% women) with mean age 54±9 years and 47% with hypertension. We observed variability in carotid-femoral pulse wave velocity and peak O2 pulse across individuals with clinically defined exercise hypertension (peak systolic BP [SBP] in men ≥210 mm Hg; in women ≥190 mm Hg). Despite similar resting SBP and cardiometabolic profiles, individuals with higher peak O2 pulse displayed higher peak SBP (P≤0.017) alongside higher fitness levels (P<0.001), suggesting that high peak exercise SBP in the context of high peak O2 pulse may in fact be favorable. Although both higher (favorable) O2 pulse and higher (adverse) arterial stiffness were associated with greater peak SBP (P<0.0001 for both), the magnitude of association of carotid-femoral pulse wave velocity with peak SBP was higher in women (sex-carotid-femoral pulse wave velocity interaction P<0.0001). In sex-specific models, exercise SBP measures accounting for workload (eg, SBP during unloaded exercise, SBP at 75 watts, and SBP/workload slope) were directly associated with the adverse features of greater arterial stiffness and lower peak O2 pulse.ConclusionsHigher peak exercise SBP reflects a complex trade-off between arterial stiffness and cardiac-peripheral performance that differs by sex. Studies of BP responses to exercise accounting for vascular and cardiac physiology may illuminate mechanisms of hypertension and clarify clinical interpretation of exercise BP.

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20-HETE and blood pressure regulation: clinical implications.

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20-HETE and blood pressure regulation: clinical implications.

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