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Angiotensin II Upregulates CAPON Expression via ERK‐MAPK‐CREB Pathway in the Paraventricular Nucleus of Rats with Chronic Heart Failure
Author(s) -
Sharma Neeru,
Zheng Hong,
Liu Xuefei,
Patel Kaushik
Publication year - 2015
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.29.1_supplement.987.7
Subject(s) - capon , creb , mapk/erk pathway , angiotensin ii , nitric oxide synthase , medicine , protein kinase a , endocrinology , kinase , biology , receptor , chemistry , nitric oxide , microbiology and biotechnology , transcription factor , biochemistry , gene , beamforming , statistics , mathematics
Elevated levels of angiotensin II (Ang II) and its receptor (AT1) in brain are responsible for increase sympatho‐excitation during heart failure (HF).Previously, we have demonstrated that higher levels of CAPON (nitric oxide synthase 1‐adaptor protein) down regulate neuronal nitric oxide synthase (nNOS) in the paraventricular nucleus (PVN) of rats with HF. The significant increase in CAPON transcript (15 folds) in the PVN of HF rats was ameliorated by Losartan treatment (10 mg/kg/day for three weeks), suggesting the involvement of AngII/AT1R signaling in transcriptional up‐regulation of CAPON. In vitro studies using NG108 cells showed that Ang II dependent increases in CAPON expression was abrogated in presence of the mitogen‐activated protein kinase/ERK kinase 1/2 inhibitor U0126. The in silico analysis of the ~7.5 kb upstream DNA sequences from the translational start site of CAPON genes identified two likely promoter elements (Promoter 2.0 Prediction Server) containing the sequences responsive (TES Software) to transcriptional factor CREB binding. Concurrently, there was activation of ERK and CREB transcriptional factors in the PVN of rats with HF as evident by increased ERK‐P/ERK (1.43±0.1 Sham. vs. 1.98±0.1 HF) and CREB‐P/CREB (1.07±0.03 Sham. vs. 1.56±0.05 HF) ratios. The siRNA‐mediated silencing of ERK and CREB in NG108 cells ameliorate Ang II mediated upregulation of CAPON further supporting the involvement of MAP kinase in facilitating CAPON up‐regulation. Taken together, our results demonstrate the involvement of the ERK1/2 pathway in selective up‐regulation of CAPON expression, possibly via activation of CREB.