Abstract P062: Interaction Of Cytochrome P450 1B1 And 12/15 Lipoxygenase In Paraventricular Nucleus In The Regulation Of Angiotensin II-induced Hypertension In Female Mice

Recently, we showed that 17β-estradiol (E2)-cytochrome P450 (CYP) 1B1-generated metabolite 2-methoxyestradiol (2-ME) in the paraventricular nucleus (PVN) protects from angiotensin (Ang) II-induced hypertension. Moreover, we showed that 2-ME produces this action by inhibiting the cytosolic phospholipase (cPLA) 2 α/arachidonic acid (AA)-cyclooxygenase (COX)-generated metabolites prostaglandin (PG)E 2 and thromboxane (TX)A 2 exerting prohypertensive effects via prostanoid receptors EP1, EP3, and TP, respectively, in female mice. 12/15 lipoxygenase (ALOX15), which also metabolizes AA, is present in the brain in neural tissue, endothelial cells, microglia, and astrocytes. This study was conducted to determine the contribution of central 12/15 lipoxygenase (ALOX15) and its relationship to CYP1B1 in Ang II-induced hypertension in the female mice. ALOX15 knockdown in the PVN by transduction with adenovirus (Ad)-ALOX15-short hairpin (sh)RNA (200 nL, bilaterally 7.04х10 11 pfu/mL) but not its control Ad-scrambled (Scr)-shRNA (6.4х10 11 pfu/mL) produced a greater reduction in systolic blood pressure (SBP, mmHg) measured by tail-cuff in response to Ang II (700 ng/kg/min, subcutaneous, osmotic pump, two weeks) in intact Cyp1b1 knockout (KO, E2 present but lacking 2-ME) than wild-type (WT, endogenous E2 and 2-ME present) female mice (Day 12: 177±4 vs 143±1 and 133±3 vs 124±1, respectively, P<0.05, n=4/group). Moreover, administration of ALOX15-generated AA metabolite 12(S)-hydroxyeicosatetraenoic acid (HETE) in a dose (50 ng/ 2 μL/ every 3rd day, intracerebroventricularly) that did not alter the mean arterial pressure (MAP) alone produced a greater increase in MAP in response to Ang II in ovariectomized (both E2 and 2-ME are lacking) than intact Alox15 KO female mice (Day 0 vs Day 12: 103±4 vs 167±2 and 103±2 vs 128±1, respectively, P<0.05, n=4/group). These results suggest that E2, via its CYP1B1-derived metabolite 2-ME, inhibits the generation of ALOX15/AA metabolite 12(S)-HETE in the brain to protect against Ang II-induced hypertension in female mice. Thus, 2-ME and/or ALOX15/12(S)-HETE inhibitors could be useful for treating hypertension and its pathogenesis in females.