The T8590C Polymorphism of CYP4A11 and 20-Hydroxyeicosatetraenoic Acid in Essential Hypertension

Abstract

Abstract-A role for a deficit in transport actions of 20-hydroxyeicosatetraenoic acid (20-HETE) in hypertension is supported by the following: (1) diminished renal 20-HETE in Dahl-S rats; (2) altered salt-and furosemide-induced 20-HETE responses in salt-sensitive hypertensive subjects; and (3) increased population risk for hypertension in C allele carriers of the T8590C polymorphism of CYP4A11, which encodes an enzyme with reduced catalytic activity. We determined T8590C genotypes in 32 hypertensive subjects, 25 of whom were phenotyped for salt sensitivity of blood pressure and insulin sensitivity. Urine 20-HETE was lowest in insulin-resistant, salt-sensitive subjects (Fϭ5.56; PϽ0.02). Genotypes were 13 TT, 2 CC, and 17 CT. C allele frequency was 32.8% (blacks: 38.9%; whites: 25.0%). C carriers (CCϩCT) and TT subjects were similarly distributed among salt-and insulin-sensitivity phenotypes. C carriers had higher diastolic blood pressures and aldosterone:renin and waist:hip ratios but lower furosemide-induced fractional excretions of Na and K than TT. The T8590C genotype did not relate to sodium balance or pressure natriuresis. However, C carriers, compared with TT, had diminished 20-HETE responses to salt loading after adjustment for serum insulin concentration and resetting of the negative relationship between serum insulin and urine 20-HETE to a 1-g/h lower level of 20-HETE. The effect of C was insulin independent and equipotent to 18 U/mL of insulin (⌬20-HETEϭ 2.84Ϫ0.054ϫinsulinϪ0.98ϫC; r 2 ϭ0.53; Fϭ11.1; PϽ0.001). Hence, genetic (T8590C) and environmental (insulin) factors impair 20-HETE responses to salt in human hypertension. We propose that genotype analyses with sufficient homozygous CC will establish definitive relationships among 20-HETE, salt sensitivity of blood pressure, and insulin resistance. Key Words: hypertension Ⅲ obesity Ⅲ arachidonic acid Ⅲ cytochrome P450 Ⅲ insulin Ⅲ insulin resistance T he monooxygenase derivative of arachidonic acid synthesized by CYP450 enzymes, 20-hydroxyeicosatetraenoic acid (20-HETE), is a candidate for participation in blood pressure regulation and hypertension. This could be via excess of its potent vasoconstrictor actions 1-4 or deficiency of its inhibition of tubular transport, normally exerted at the NKCC cotransporter of the thick ascending limb and at the ubiquitous renal tubular Na-K-ATPase. [5][6][7][8] Studies in Dahl-S rats 9 -11 and in angiotensin II-induced hypertension in mice 12 support the view that a diminished effect of 20-HETE on renal transport is an important mechanism in experimental hypertension. Human population studies on polymorphisms of CYP4A11 that diminish its catalytic activity to synthesize 20-HETE 13,14 are consistent with this interpretation.Our studies in essential hypertension documented abnormal 20-HETE responses to physiological 15 and pharmacological 16 natriuresis and negative relationships with serum insulin 17 but not diminished urinary excretion of 20-HETE, as expected from observations in rodents. Because Dahl-S rats are not ...

Activation of Neuronal Transient Receptor Potential Vanilloid 1 Channel Underlies 20-Hydroxyeicosatetraenoic Acid–Induced Vasoactivity

“…In addition, elevations of 20-HETE levels and activity have been implicated in a diverse range of preclinical models of cardiovascular disease, 22,47,48 as well as in human disease, particularly hypertension. 22,[49][50][51] Collectively, such observations, coupled with our findings presented herein, support the notion that exploration of the therapeutic potential of TRPV1 antagonists beyond inflammatory pain into the cardiovascular realm may yield substantial benefits.…”

The V433M Variant of the CYP4F2 Is Associated With Ischemic Stroke in Male Swedes Beyond Its Effect on Blood Pressure

“…5 Moreover, CYP4A11 S-carriers showed higher aldosterone:renin and waist:hip ratios but lower furosemide-induced fractional excretions of Na ϩ and K ϩ versus F434F homozygotes, probably because of a diminished 20-HETE responses to salt loading, after adjustment for the serum insulin concentration. 7 Here, we found that the CYP4A11 F434S and the CYP4F2 V433M polymorphisms in the gene codifying for the 2 major 20-HETE metabolizing enzymes in the kidney are associated with BP levels and hypertension. We speculate that, as suggested from in vitro experiments, in our sample, a diminished production of 20-HETE at tubular level could have impaired the capacity of the kidney to excrete salt, indeed heightening BP levels and predisposing to hypertension.…”

Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation?

“…[75] Carriers of the same polymorphism have higher aldosterone/renin and waist/hip ratios and lower furosemide-induced fractional excretions of sodium and potassium than 8590TT homozygotes [76]. All these data are coherent with the selective localization of CYP4A11 in the S2 and S3 segments of proximal tubule epithelia in the cortex and outer medulla [77], so that a decreased catalytic activity should result in the reduction of 20-HETE formation and a consequent decrease in natriuresis.…”