Abstract 79: Knockdown of ACE2 in the Paraventricular Nucleus Partially Reverses the Protective Effects of Brain ACE2 in DOCA-salt Hypertension
To identify which brain regions are critical for ACE2 regulation of blood pressure (BP), we generated transgenic mice harboring a loxP-flanked human ACE2 transgene specifically in the brain (hACE2flox) and tested the impact on DOCA-salt hypertension. hACE2flox and non-transgenic (NT) mice were implanted with telemetry probes for conscious BP monitoring. DOCA (1 mg/g, sc) was implanted following baseline BP recording and drinking water was replaced by 1% NaCl solution. Two weeks later, hACE2flox mice were divided into 2 groups (n=7/group) and injected bilaterally with an adenovirus encoding Cre recombinase (Ad-Cre) or a control virus (LacZ) to the paraventricular nucleus (PVN; 107 particles/200 nl; ±0.3 mm lateral, 0.6 mm caudal, 5.0 mm ventral). NT mice were also injected with LacZ. BP was continuously recorded for 1 more week. Autonomic function was analyzed using a pharmacological method involving ip injection of propranolol (4 mg/kg) and atropine (1 mg/kg). Changes in heart rate (ΔHR, bpm) were used as index of sympathetic and parasympathetic tones. Baseline mean BP was not different among NT+LacZ (105 ±3 mmHg), hACE2flox+LacZ (107 ±2 mmHg) and hACE2flox+Ad-Cre (106 ±2 mmHg) groups, nor was sympathetic (-91 ±4, -101 ±8, -101 ±14 bpm) or vagal tones (+169 ±7, +152 ±10, +168 ±9 bpm). Three weeks after DOCA-salt treatment, mean BP was dramatically increased in NT+LacZ mice (141 ±3 mmHg, P<0.01 vs. baseline) but only modestly increased in hACE2flox+LacZ mice (127 ±4 mmHg, P<0.05 vs. NT). In addition, cardiac sympathetic drive was significantly increased (-193 ±27 bpm, P<0.01 vs. baseline) while vagal tone was impaired (+113 ±11 bpm) in NT+LacZ mice. However, DOCA-salt-mediated autonomic dysfunction was prevented in hACE2flox+LacZ mice (sympathetic drive: -119 ±7 bpm, vagal tone: +146 ±9 bpm, P<0.05 vs. NT+LacZ). Selective knockdown of ACE2 in the PVN by Ad-Cre tended to increase BP (133 ±3 mmHg) and sympathetic activity (-168 ±35 bpm) as well as decrease vagal tone (+138 ±34 bpm) in hACE2flox, compared to LacZ transfected hACE2flox mice. These data suggest that ACE2 overexpression in the brain blunts the development of hypertension by preventing autonomic dysfunction, and PVN might not be essential for the ACE2-mediated blunting of neurogenic hypertension.
- © 2012 by American Heart Association, Inc.