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Exercise Training Augments Neuronal Nitric Oxide Synthase Dimerization in the Paraventricular Nucleus of Rats with Heart Failure
Author(s) -
Sharma Neeru,
Liu Xuefei,
Llewellyn Tamra,
Patel Kaushik P
Publication year - 2017
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.31.1_supplement.687.12
Subject(s) - tetrahydrobiopterin , medicine , nitric oxide synthase , heart failure , nitric oxide , endocrinology , enos , chemistry
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, possibly due to reduced neuronal nitric oxide synthase (nNOS) within the paraventricular nucleus (PVN). Previously we have demonstrated that during CHF, the catalytically active dimeric form of nNOS is significantly decreased (~40% decrease in dimer/monomer ratio) with a simultaneous increase in PIN expression (~50%), a protein that uncouples dimeric nNOS to monomers and facilitates its degradation. Dimerization of nNOS also requires tetrahydrobiopterin (BH4) for stability and activity. We have also shown that ExT improves NO‐mediated sympathoinhibition from the PVN. However, the underlying molecular mechanism remains unclear. We hypothesized that ExT restores the sympathetic drive by normalization of the levels and catalytically active form of nNOS by abrogating changes in PIN within the PVN of rats with CHF. 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, Sham and CHF rats were subjected to 3–4 weeks of progressive treadmill exercise. ExT significantly (p < 0.05) restored PIN expression (0.68±0.05 CHF vs 0.40±0.06* ExT‐CHF), and normalized dimer/monomer ratio (0.67±0.04 CHF vs 0.90±0.07* ExT‐CHF), 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 (0.74±0.03 Sham vs. 0.48±0.02* CHF), suggesting that perhaps reduced BH4 availability may also contribute to decreased nNOS dimer formation. Interestingly, CHF induced reduction in GCH1 expression was improved with ExT (0.48±0.02 CHF vs. 0.70±0.07* ExT‐CHF). Taken together, our findings revealed that ExT‐rectified, decreased PIN and GCH1 expression and improved dimer/monomer ratio of nNOS in the PVN, resulting in increased NO which ameliorates the enhanced sympathetic drive in CHF. Support or Funding Information Supported by AHA‐14SDG19980007 and NIH HL62222.