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Contribution of PIN in the regulation of neuronal nitric oxide synthase in the PVN of Rats with chronic heart failure
Author(s) -
Sharma Neeru,
Llewellyn Tamra,
Zheng Hong,
Patel Kaushik P
Publication year - 2012
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.26.1_supplement.703.17
Subject(s) - lactacystin , nitric oxide synthase , chemistry , downregulation and upregulation , nitric oxide , proteasome , medicine , neuronal nitric oxide synthase , endocrinology , gene knockdown , angiotensin ii , proteasome inhibitor , biochemistry , receptor , apoptosis , gene
Expression of neuronal nitric oxide synthase (nNOS) decreased in the paraventricular nucleus (PVN) of rats with chronic heart failure (CHF), however the molecular mechanism remains unclear. In the present study protein levels of PIN (a protein inhibitor of nNOS, known to dissociate nNOS dimers into monomers) increased (1.12±0.09 vs. Sham 0.76±0.10) with approximately 60% decrease in dimer/monomer ratio in the PVN of rats with CHF (6–8 wks. after coronary artery ligation). In vitro studies using neuronal cell line, NG108 showed that PIN protein expression is 2.3‐ fold higher in response to angiotensin II (Ang II). Silencing of PIN in NG108 cells leads to 2‐fold accumulation of nNOS suggesting a regulatory role of PIN in NO synthesis. Moreover, dimer/monomer ratio of nNOS also increased by 80% with PIN knockdown in NG108 cells. Furthermore, Ang II treatment in NG108 cells in the presence of proteasome inhibitor, lactacystin, led to decreased ubiquitination of PIN (54% decrease vs. lactacystin alone), suggesting that posttranslational processes such as protein degradation/stabilization are involved in Ang II dependent upregulation of PIN. We conclude that post‐translational accumulation of PIN, mediated by Ang II, leads to a decrease in the dimeric active form of nNOS as well as protein levels of nNOS which may lead to reduced nitric oxide mediated inhibition of sympathetic tone during CHF. Supported by NIH grant HL62222