Androgen-sensitive hypertension associated with soluble guanylate cyclase-alpha_1 deficiency is mediated by 20-HETE

摘要

Dysregu-lated nitric oxide (NO) signaling contributes to the pathogenesis of hypertension, a prevalent and often sex-specific risk factor for cardiovascular disease. We previously reported that mice deficient in the alpha_1-subunit of the NO receptor soluble guanylate cyclase (sGCalpha_1~(-/-) mice) display sex- and strain-specific hypertension: male but not female sGCalpha_1~(-/-) mice are hypertensive on an 129S6 (S6) but not a C57BL6/J (B6) background. We aimed to uncover the genetic and molecular basis of the observed sex- and strain-specific blood pressure phenotype. Via linkage analysis, we identified a suggestive quantitative trait locus associated with elevated blood pressure in male ssGCalpha_1~(-/-) S6 mice. This locus encompasses Cyp4al2a, encoding the predominant murine synthase of the vasoconstrictor 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE). Renal expression of Cyp4al2a in mice was associated with genetic background, sex, and testosterone levels. In addition, 20-HETE levels were higher in renal preglomerular microvessels of male sGCalpha_1~(-/-) S6 than of male sGCalpha_1~(-/-) B6 mice. Furthermore, treating male sGCalpha_1~(-/-) S6 mice with the 20-HETE antagonist 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) lowered blood pressure. Finally, 20-HEDE rescued the genetic background- and testosterone-dependent impairment of acetylcholine-induced relaxation in renal interlobar arteries associated with sGCalpha_1 deficiency. Elevated Cyp4a12a expression and 20-HETE levels render mice susceptible to hypertension and vascular dysfunction in a setting of sGCalpha_1 deficiency. Our data identify Cyp4a12a as a candidate sex-specific blood pressure-modifying gene in the context of deficient NO-sGC signaling.