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Brain targeted ACE2 overexpression prevents DOCA‐salt hypertension and cardiac hypertrophy by modulating NOS and ERK1/2 phosphorylation
Author(s) -
Sriramula Srinivas,
Xia Huijing,
Lazartigues Eric
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.927.7
Subject(s) - medicine , endocrinology , enos , muscle hypertrophy , chemistry , phosphorylation , fibrosis , saline , myocardial fibrosis , nitric oxide synthase , nitric oxide , biochemistry
Angiotensin Converting Enzyme 2 (ACE2) overexpression in the brain prevents the development of DOCA‐salt hypertension in syn‐hACE2 (SA) transgenic mice. We hypothesized that the NOS‐ERK1/2 pathway mediates ACE2 beneficial effects. DOCA‐salt treatment (1 mg/g body weight DOCA, 1% saline in drinking water, 3 wks) 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). Cardiac hypertrophy (heart weight/body weight: 5.6 ±0.2 vs. 4.6 ±0.1, p<0.01; heart weight/tibia length: 9.4 ±0.7 vs. 7.6 ±0.3, p<0.01) was also attenuated in SA+DOCA mice. Cardiac interstitial fibrosis (picrosirius red staining) was attenuated in SA+DOCA compared to NT+DOCA mice (% area, 0.6 ±0.1 vs. 1.9 ±0.3, p<0.01). NT+DOCA mice showed a reduction of phosphorylated eNOS/total eNOS (30 ±3 % decrease, n=9, p<0.05 vs. NT) and nNOS (26 ±7 % decrease, n=9, p<0.05 vs. NT) in the paraventricular nucleus (PVN), that could be prevented by ACE2 overexpression (14 ±3 and 35 ±6 % increases, respectively, p<0.05). Furthermore, phosphorylation of ERK1/2 was increased in the PVN of NT+DOCA (50 ±11 % increase, n=9, p<0.01 vs. NT), which was attenuated in SA+DOCA mice (30 ±4 % decrease, p<0.01). Taken together, these data provide evidence that brain ACE2 regulates hypertensive and hypertrophic effects via modulation of NOS‐ERK1/2 phosphorylation.