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20‐SOLA, a Novel Water Soluble 20‐HETE Antagonist, Reduces Blood Pressure Through Regulation of Vascular ACE Expression via an IKK Dependent Pathway
Author(s) -
Garcia Victor,
Shkolnik Brian,
Pandey Varun,
Capdevila Jorge,
Falck John,
Schwartzman Michal
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.647.9
Subject(s) - endocrinology , medicine , antagonist , blood pressure , angiotensin ii , renin–angiotensin system , chemistry , vascular smooth muscle , receptor , smooth muscle
Increased vascular 20‐HETE has been associated with hypertension and activation of the renin‐angiotensin system through induction of vascular angiotensin converting enzyme (ACE) expression. CYP4a14 knockout (KO) mice exhibit male‐specific androgen‐sensitive 20‐HETE‐dependent hypertension. A novel water‐soluble 20‐HETE antagonist, 2,5,8,11,14,17‐hexaoxanonadecan‐19‐yl 20‐hydroxyeicosa‐6(Z),15(Z)‐dienoate (20‐SOLA) was administered to CYP4a14 KO male and female mice (10mg/kg/day in drinking water). 20‐SOLA normalized blood pressure in hypertensive CYP4a14 KO male mice over the course of 10 days (124±1 vs 153 ±2 mmHg in untreated littermates) and had no effect on blood pressure of CYP4a14 KO female mice (126±1 vs 124±1 mmHg). Renal preglomerular microvessel (PGMV) ACE expression was significantly elevated in CYP4a14 KO males (3.57 ± 0.6 fold) compared to normotensive female mice and treatment with 20‐SOLA normalized vascular ACE expression. 20‐HETE‐mediated induction of vascular endothelial ACE expression has been demonstrated to be IKK‐dependent. PGMV of CYP4a14 KO male mice expressed a 2.6‐fold increase in phospho‐IKK compared to female KO mice and this increase was significantly reduced by 20‐SOLA (2.6±0.2 vs. 1.3±0.3 fold, respectively). These results suggest that the water soluble 20‐HETE antagonist 20‐SOLA reduces blood pressure in the male CYP4a14 KO mice, at least in part, through regulation of vascular ACE expression.