RGD Reference Report - Exercise training augments neuronal nitric oxide synthase dimerization in the paraventricular nucleus of rats with chronic heart failure. - Rat Genome Database

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Exercise training augments neuronal nitric oxide synthase dimerization in the paraventricular nucleus of rats with chronic heart failure.

Authors: Sharma, Neeru M  Liu, Xuefei  Llewellyn, Tamra L  Katsurada, Kenichi  Patel, Kaushik P 
Citation: Sharma NM, etal., Nitric Oxide. 2019 Jun 1;87:73-82. doi: 10.1016/j.niox.2019.03.005. Epub 2019 Mar 13.
RGD ID: 329961332
Pubmed: PMID:30878404   (View Abstract at PubMed)
PMCID: PMC6527363   (View Article at PubMed Central)
DOI: DOI:10.1016/j.niox.2019.03.005   (Journal Full-text)

Exercise training (ExT) is an established non-pharmacological therapy that improves the health and quality of life in patients with chronic heart failure (CHF). Exaggerated sympathetic drive characterizes CHF due to an imbalance of the autonomic nervous system. Neuronal nitric oxide synthase (nNOS) in the paraventricular nucleus (PVN) produce nitric oxide (NO•), which is known to regulate the sympathetic tone. Previously we have shown that during CHF, the catalytically active dimeric form of nNOS is significantly decreased with a concurrent increase in protein inhibitor of nNOS (PIN) expression, a protein that dissociates dimeric nNOS to monomers and facilitates its degradation. Dimerization of nNOS also requires (6R)-5,6,7,8-tetrahydrobiopterin (BH4) for stability and activity. Previously, we have shown that ExT improves NO-mediated sympathetic inhibition in the PVN; however, the molecular mechanism remains elusive. We hypothesized; ExT restores the sympathetic drive by increasing the levels and catalytically active form of nNOS by abrogating changes in the PIN in the PVN of CHF rats. CHF was induced in adult male Sprague-Dawley rats by coronary artery ligation, which reliably mimics CHF in patients with myocardial infarction. After 4 weeks of surgery, Sham and CHF rats were subjected to 3 weeks of progressive treadmill exercise. ExT significantly (p < 0.05) decreased PIN expression and increased dimer/monomer ratio of nNOS in the PVN of rats with CHF. Moreover, we found decreased GTP cyclohydrolase 1(GCH1) expression: a rate-limiting enzyme for BH4 biosynthesis in the PVN of CHF rats suggesting that perhaps reduced BH4 availability may also contribute to decreased nNOS dimers. Interestingly, CHF induced decrease in GCH1 expression was increased with ExT. Our findings revealed that ExT rectified decreased PIN and GCH1 expression and increased dimer/monomer ratio of nNOS in the PVN, which may lead to increase NO• bioavailability resulting in amelioration of activated sympathetic drive during CHF.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
congestive heart failure treatmentISOGch1 (Rattus norvegicus)329961332; 329961332 RGD 
congestive heart failure treatmentIEP 329961332 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gch1  (GTP cyclohydrolase 1)

Genes (Mus musculus)
Gch1  (GTP cyclohydrolase 1)

Genes (Homo sapiens)
GCH1  (GTP cyclohydrolase 1)


Additional Information