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)

Angiotensin‐converting enzyme 2 in the brain: properties and future directions

“…2008b). In addition, using this adenovirus, we showed that over‐expression of ACE2 in the paraventricular nucleus attenuates the increased sympathetic vasomotor tone resulting from Ang‐II infusion in ACE2 −/y mice, and reduced the associated oxidative stress in the paraventricular nucleus and downstream nuclei (Xia et al. 2008).…”