RGD Reference Report - Angiotensin II-mediated post-translational modification of nNOS in the PVN of rats with CHF: Role for PIN. - Rat Genome Database

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Angiotensin II-mediated post-translational modification of nNOS in the PVN of rats with CHF: Role for PIN.

Authors: Sharma, NM  Llewellyn, T  Zheng, H  Patel, KP 
Citation: Sharma NM, etal., Am J Physiol Heart Circ Physiol. 2013 Jul 5.
RGD ID: 7257598
Pubmed: PMID:23832698   (View Abstract at PubMed)
PMCID: PMC3761348   (View Article at PubMed Central)
DOI: DOI:10.1152/ajpheart.00170.2013   (Journal Full-text)

An increased sympathetic drive is an adverse characteristic in chronic heart failure (CHF). The protein expression of neuronal nitric oxide synthase (nNOS) and hence nitric oxide (NO) mediated sympathoinhibition is reduced in the paraventricular nucleus (PVN) of rats with CHF. However, the molecular mechanism(s) of nNOS downregulation remain(s) unclear. The aim of the study was to reveal the underlying molecular mechanism for the downregulation of nNOS in the PVN of CHF rats. Sprague-Dawley rats with CHF (6-8 weeks after coronary artery ligation) demonstrated decreased nNOS dimer/monomer ratio (42%), with a concomitant increase in the expression of PIN (a protein inhibitor of nNOS known to dissociate nNOS dimers into monomers) by 47% in the PVN. Similarly, PIN expression is increased in a neuronal cell line (NG108) treated with angiotensin II (Ang II). Furthermore, there is an increased accumulation of high molecular weight nNOS-ubiquitin (nNOS-Ub) conjugates in the PVN of CHF rats (29%). Ang II treatment in NG108 cells in the presence of a proteasome inhibitor, lactacystin, also leads to a 69% increase in accumulation of nNOS-Ub conjugates immunoprecipitated by an anti-ubiquitin antibody. There is an Ang II-driven, PIN- mediated decrease in the dimeric catalytically active nNOS in the PVN, due to ubiquitin-dependent proteolytic degradation in CHF. Our results show a novel intermediary mechanism which leads to decreased levels of active nNOS in the PVN, involved in subsequent reduction in sympathoinhibition during CHF, offering a new target for the treatment of CHF and other cardiovascular diseases.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
DYNLL1Humancongestive heart failure  ISODynll1 (Rattus norvegicus)protein:increased expression:paraventricular nucleusRGD 
Dynll1Ratcongestive heart failure  IEP protein:increased expression:paraventricular nucleusRGD 
Dynll1Mousecongestive heart failure  ISODynll1 (Rattus norvegicus)protein:increased expression:paraventricular nucleusRGD 
NOS1Humancongestive heart failure  ISONos1 (Rattus norvegicus) RGD 
Nos1Ratcongestive heart failure  IEP  RGD 
Nos1Mousecongestive heart failure  ISONos1 (Rattus norvegicus) RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Nos1Ratidentical protein binding  IPINos1 (Rattus norvegicus)homodimerizationRGD 

Objects Annotated

Genes (Rattus norvegicus)
Dynll1  (dynein light chain LC8-type 1)
Nos1  (nitric oxide synthase 1)

Genes (Mus musculus)
Dynll1  (dynein light chain LC8-type 1)
Nos1  (nitric oxide synthase 1, neuronal)

Genes (Homo sapiens)
DYNLL1  (dynein light chain LC8-type 1)
NOS1  (nitric oxide synthase 1)


Additional Information