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

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 (F=5.56; P r ² =0.53; F=11.1; P <0.001). 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.