ACE2 over‐expression regulates oxidative stress gene expression in the brainstem

Abstract

Angiotensin (Ang) I converting enzyme type 2 (ACE2) cleaves Ang II into the vasodilator Ang‐(1–7). We previously reported that ACE2 is expressed in the brain and involved in the prevention of hypertension via regulation of autonomic function. We also showed that ACE2 KO mice have increased levels of reactive oxygen species (ROS) in the brain. To clarify the role of ACE2 in the regulation of ROS levels, we performed an oxidative stress PCR array using brainstems from SA mice, with brain‐specific ACE2 overexpression, and control littermates (NT).In SA mice, the main ROS‐producing enzyme, NADPH oxidase, subunits genes Nox1 (gp91phox homolog), Nox4, p22phox and p67phox were downregulated by −3.1, −1.6, −13.4 and −11 folds respectively, compared to controls. The NADPH oxidase activator 1 (Noxa1) and the dual oxidase1 (Duox1), which generates hydrogen peroxide, were also decreased by −2.6 and −1 fold, respectively. Anti oxidant stress enzymes like glutathione peroxidase 1, 3, 6, 8 subunits were downregulated by −180, −3, −2.4, −3.1 folds and so were SOD 1 (−1.2 fold) and 3 (−1.8 fold). Moreover, there was a trend to a reduction in lipid peroxidation (Tbars assay) in the brainstem of SA mice. These data show that ACE2 is regulating the expression of multiple genes involved in the formation and removal of ROS in the brainstem, which may contribute to the prevention of hypertension in this model. NIH RR018766 and HL093178