Abstract 179: ACE2 Overexpression Prevents DOCA-Salt Hypertension by Modulating Cyclooxygenase Mediated Neuro-inflammation in the Central Nervous System

Abstract

DOCA-salt hypertension, a low-renin hypertension model, is mediated through activation of the renin angiotensin system within the brain and is mediated by inflammation. We previously reported that central Angiotensin Converting Enzyme 2 (ACE2) overexpression prevents the development of hypertension induced by DOCA-salt in a transgenic mouse model (syn-hACE2; SA) with human ACE2 targeted selectively to neurons. The present study examined whether ACE2 modulates cyclooxygenase (COX)-mediated neuro-inflammation in DOCA-salt-mediated hypertension. DOCA-salt treatment (1 mg/g body weight DOCA, 1% saline in drinking water, 3 weeks) of non-transgenic (NT) and SA mice produced a significant hypertension (MAP; telemetry) in NT (138 ±3 mmHg, n=8, p<0.05) that was blunted in SA mice (122 ±3 mmHg, n=12, p<0.05). NT mice treated with DOCA-salt showed increased inflammation as indicated by increased gene expression of TNF (3 fold, n=9, p<0.001 vs. NT), IL-1beta (8 fold, n=9, p<0.001 vs. NT) and IL-6 (5 fold, n=9, p<0.01 vs. NT) in the hypothalamic paraventricular nucleus (PVN) which was attenuated in SA mice. Furthermore, DOCA-salt hypertension resulted in increased expression of COX-1 (2.5 fold, n=9, p<0.001 vs. NT) and COX-2 in the PVN (5 fold, n=9, p<0.05 vs. NT) and this increase was prevented by ACE2 overexpression. ACE2 overexpression also prevented DOCA-salt induced increases in EP1 (1.5 fold, n=9, p<0.01 vs. NT) and EP3 (1.5 fold, n=9, p<0.01 vs. NT) receptors expression in the PVN. Taken together, these data provide evidence that brain ACE2 prevents COX mediated neuro-inflammation, thereby preventing the development of DOCA-salt hypertension.