Metabolites of arachidonic acid via CYP450 in human hypertension

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Background: In the last years there has been considerable interest in exploring the role of 20- hydroxyeicosatetraenoic acid (20-HETE) and 5,6-, 8,9-, 11,12- and 14,15 epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid via cythochrome P450 (CYP), in hypertension, given the importance of this pathway in the regulation of renal and peripheral vascular tone and the renal handling of sodium. The CYP4A11 and the CYP4F2 are responsible for renal production of 20-HETE. The CYP4A11 F434S and CYP4F2 V433M polymorphisms reduce 20- HETE production, in vitro. Aims: The aim of the first study was to investigate whether activation of the renin angiotensin system in renovascular disease affects the CYP ω-ω-1 hydroxylase (20-HETE) and epoxygenase (EETs) pathways of arachidonic acid metabolism in vivo, each of which interacts with Angiotnsin II (study 1). The aim of the second study was to evaluate the effect of the mentioned polymorphisms on blood pressure (BP) levels, hypertension prevalence and cardiovascular events in a large cohort of middle-aged Swedes (study 2). Methods: Plasma concentration and urinary excretion of 20-HETE, and EETs and their metabolites, dihydroxyeicosatrienoic acids (DHETs), were measured in urine and plasma by mass spectrometry in 10 subjects with renovascular disease, 10 with essential hypertension, and 10 healthy normotensive subjects (controls), pair-matched for gender and age. Vascular and renal function was evaluated in all subjects (study 1). The polymorphisms were genotyped in the cardiovascular cohort of the Malmö Diet and Cancer (MDC-CVA) study. The incidence of fatal and non-fatal cardiovascular events (coronary events, n= 268, and ischemic stroke, n =194) was monitored over 10 years of follow-up. The analysis of blood pressure levels was performed twice: excluding subjects under antihypertensive treatment and including them (study 2). Results: Plasma 20-HETE was highest in subjects with renovascular disease [1.20 (0.42-1.92) ng/mL, median and range] compared to essential hypertensives [0.90 ng/mL (0.40-2.1)] and Metabolites of arachidonic acid via CYP450 in human hypertension controls [0.45 ng/mL (0.14-1.7), P<0.05]. Plasma 20- HETE significantly correlated with plasma renin activity (PRA) in renovascular disease (rs=0.67, n=10, P<0.05). The urinary excretion of 20-HETE was significantly lower in subjects with renovascular disease [12.9, (4.4-24.9) μg/g creatinine] than in controls [31.0 (11.9-102.8) μg/g creatinine, P<0.01)] and essential hypertensives [35.9 (14-72.5) μg/g creatinine, P<0.05]. Total plasma EETs were lowest as was the ratio of plasma EETs to plasma DHETs, an index of epoxide hydrolase activity, in renovascular disease [ratio 2.4 (1.2-6.1)], compared to essential hypertension [3.4 (1.5-5.6)] and controls [6.8 (1.4-18.8), P<0.01] (study 1). In the whole population, CYP4A11 S434S homozygotes had higher adjusted (for number of antihypertensive drugs) and non-adjusted systolic BP and higher prevalence of hypertension respect to F434 carriers. Male but not female CYP4F2 M433 carriers had significantly higher adjusted and non-adjusted systolic and diastolic BP and a trend toward higher hypertension prevalence (p=0.06) respect to V433V homozygotes. After adjustment for major cardiovascular risk factors, the hazard ratio (HR) for ischemic stroke in male CYP4F2 M433 carriers was significantly higher respect to V433V homozygotes (HR 1.69; 95%C.I. 1.1-2.6) even when BP levels and hypertension prevalence were included in the COX proportional-hazard model (study 2). Conclusion: circulating levels of 20-HETE are increased and those of EETs are decreased in RVD, while the urinary excretion of 20-HETE is reduced. Altered CYP 450 arachidonic acid metabolism may contribute to the vascular and tubular abnormalities of RVD (study 1). A common V433M polymorphism of the CYP4F2 might increase the risk of incident ischemic stroke in males but only partially through its elevating effect on BP. Further studies are needed to confirm these data (study 2).