ACE2 Inhibits Angiotensin‐II Mediated NADPH Oxidase Activation In The Central Nervous System

Abstract

ACE2 plays a protective role in the central regulation of autonomic function by reducing oxidative stress. To assess the mechanisms involved, ACE2 KO and non transgenic (NT) mice (n=6) were infused with AngII (osmotic pump: 600 ng/kg/min sc) and infected with a hACE2 or control (eGFP) adenovirus (2×106 pfu, 200 nL) in the PVN 3d post infusion. After 10d of infusion, NADPH oxidase (NOX) and superoxide dismutase (SOD) activity (U/mg), and SOD 1 and 2 protein expression (Immunofluorescence, arbitrary units) were assessed in the brainstem. NOX (2.8 ±0.1 vs. 1.0 ±0.02) and SOD activities (1.4 ±0.1 vs. 1.0 ±0.05; P<0.05) were significantly increased in KO mice (P<0.05 vs. NT), as well as SOD1 (2.5 ±0.6 vs. 1.0 ±0.04) and SOD2 (1.7 ±0.1 vs. 1.0 ±0.05) expression (P<0.05 vs. NT). Post AngII, NOX activity was increased in both KO (3.1 ±0.2) and NT (2.1 ±0.2) and remained higher in the KO (P<0.05 vs. NT), while SOD1 and 2 expression and activity were only increased in the NT (2.3±0.6; 1.6±0.1; 1.2±0.1; respectively, P<0.05 vs. baseline). ACE2 over‐expression reduced NOX activity in the KO without changing SOD expression or activity. These data suggest that ACE2 gene deletion promotes AngII‐mediated oxidative stress, and ACE2 compensation in the PVN decreases oxidative stress in the brainstem by inhibiting NOX activation, thus contributing to the improvement of autonomic function in this model. (HL093178 and APS Postdoctoral Fellowship)