ACE2 prevention of oxidative stress in the brain is associated with a reduction in Angiotensin II‐induced sympathetic vasomodulation

Abstract

We previously reported the presence of Angiotensin Converting Enzyme type 2 (ACE2) in brain regions involved in cardiovascular regulation. Here we test the role of central ACE2 on oxidative stress and autonomic function. ACE2 knockout (KO) mice (n=3/group) were infected with a hACE2 or control (eGFP) adenovirus (2×10e6 pfu, 200 nL) in the paraventricular nucleus (PVN) 3d before AngII infusion (osmotic pump: 600 ng/kg/min sc). After 4d infusion, mice were injected with dihydroethidium (DHE) intracardially and staining measured in brain regions (Image J, arbitrary units). Baseline blood pressure (BP) (telemetry: 112±7 vs. 111±3 mmHg) and DHE staining in the brain were not different between ACE2 KO and wildtypes. Post infusion, AngII levels in the hypothalamus were significantly higher in KO vs. wildtype mice (RIA: 2.9±0.3 vs. 2.0±0.2 fmol/mg, n=5, P<0.05) and DHE fluorescence in KO (eGFP‐infected) dramatically increased (P<0.01) vs. baseline in the PVN (194±12 vs. 101±3), NTS (52±2 vs. 20±2) and RVLM (207±22 vs. 77±12). This increase was prevented in Ad‐hACE2‐infected KO in the PVN (114±8, P<0.01) as well as in the NTS (22±2, P<0.01) and RVLM (88±8, P<0.01). Moreover, ACE2 gene therapy decreased the LF/HF ratio (BP variability) in AngII‐infused KO (5±1 vs. 9±3). These data support the protective role of ACE2 in the central regulation of autonomic function by reducing oxidative stress. (NIH NS052479 and P20RR018766)