ACE2 over‐expression decreases the development of neurogenic hypertension and is associated with activation of nitric oxide synthase and nitric oxide release in human ACE2 transgenic mice

Abstract

Central ACE2 prevents the development of hypertension induced by chronic AngII infusion in transgenic mice (SA) overexpressing ACE2 in the brain. To elucidate the mechanisms involved, we investigated the expression of NOS isoforms (immunohistochemistry) and NO release (free radical measurement) in the brain of these mice. At baseline, ACE2 over‐expression was associated with increased (Relative Intensity, RI) nNOS (1.9 ±0.4), eNOS (1.5 ±0.1), phosphorylated‐eNOS‐Ser1177/Thr495 ratio (3.4 ±0.2), an index of phosphorylation vs. dephosphorylation and NO release (3.57 ±0.02 μM) vs. non‐transgenic (NT) littermates (1.0 ±0.1 RI and 2.95 ±0.11 μM, respectively, P<0.05). AngII infusion dramatically reduced nNOS (1.4 ±0.3) and eNOS (0.8 ±0.1) expression; (P<0.05) and NO release (2.68 ±0.19 μM) in SA but it remained significantly higher than in NT (nNOS: 0.4 ±0.03; eNOS: 0.4 ±0.1; NO: 1.82 ±0.22 μM, P<0.05) mice. Interestingly, Ang II+Mas blocker dramatically decreased the Phospho‐eNOS‐Ser1177/Thr495 ratio (0.7 ±0.02) compared to SA mice infused with AngII alone (3.6 ±0.5, P<0.05) and further reduced NO levels (1.75 ±0.08 μM). These data suggest that ACE2 exerts its modulatory effects partly through up‐regulation of NOS expression and phosphorylation, reinforcing Ang‐(1–7)‐mediated NO release in the brain, thus preventing the development of neurogenic hypertension. (AHA 0825459E, NIH RR018766 and HL093178)