Abstract 15784: Increased 20-HETE Signaling Contributes to Gender- and Mouse Strain-Specific Hypertension in the Setting of Impaired NO-sGC Signaling
Introduction: Hypertension is a multifactorial disease affecting one in three adults in the US. Evidence suggests that dysregulated signaling of the vasodilator nitric oxide (NO) is involved in its pathogenesis. Previously, we reported that mice deficient in the α1 subunit of the NO receptor guanylate cyclase (sGCα1-/- mice), display gender- and strain-specific hypertension: male mice on an Sv129/J (S6) but not a C57BL6/J (B6) background are hypertensive.
Methods and Results: Via linkage analysis, we identified a quantitative trait locus (QTL) associated with elevated blood pressure in male sGCα1-/-S6 mice. This QTL encompasses the gene encoding CYP4a12a, a predominant synthase of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE) in murine kidneys. Renal CYP4a12a gene expression, assessed using qRT-PCR, was higher in male WT and sGCα1-/- S6 mice than in female S6 mice or male and female, WT and sGCα1-/- B6 mice. In addition, 20-HETE levels, measured via liquid chromatography-tandem mass spectrometry, were higher in renal preglomerular microvessels of male sGCα1-/-S6 than of male sGCα1-/-B6 mice (2.3±0.4 vs 1.6±0.4 ng/mg protein, respectively, n=5 and 3, P<0.05). Furthermore, treating male sGCα1-/-S6 mice with the 20-HETE synthesis inhibitor HET0016 (10 mg/kg/day IP for 14 days) reduced the mean arterial pressure (MAP; 130±13 mmHg in 6 HET0016-treated mice vs. 159±2 mmHg in 2 vehicle-treated mice). Similarly, administration of the 20-HETE antagonist, 20-6,15-HEDGE (20-HEDGE, 10 mg/kg IV) to male sGCα1-/-S6 mice lowered MAP in 20-HEDGE-treated but not in vehicle treated mice (delta MAP = -10±3 vs 1±2 mmHg, n=8 for both, P<0.05). Finally, the more significant impairment of acetylcholine-induced relaxation of renal interlobar arteries in male sGCα1-/-S6 than in sGCα1-/-B6 mice, was rescued by adding 20-HEDGE (10 μM).
Conclusions: Gender- and strain-specific hypertension in sGCα1-/-S6 mice is associated with elevated CYP4a12a gene expression and higher 20-HETE levels. Hypertension and vascular dysfunction in sGCα1-/-S6 mice is abrogated by 20-HETE inhibition. Our data identify CYP4a12a as a candidate blood pressure modifying gene in the context of deficient NO-sGC signaling.
Author Disclosures: S. Vandenwijngaert: None. A.C. Dordea: None. R.E. Tainsh: None. D.I. Nathan: None. M.J. Raher: None. A. Kirby: None. C. Stevens: None. M.J. Daly: None. P. Brouckaert: None. M.L. Schwartzman: None. K.D. Bloch: None. E.S. Buys: None.
- © 2014 by American Heart Association, Inc.