Abstract 17215: Exercise Training Restores Dimeric nNOS by Regulating PIN Expression in the Paraventricular Nucleus of Chronic Heart Failure Rats
Introduction and Hypothesis: Exercise training (ExT) is an established non-pharmacological therapy that improves the health and quality of life in patients with chronic heart failure (CHF). CHF is characterized by exaggerated sympathetic drive due to an imbalance of the autonomic nervous system. Neuronal nitric oxide synthases (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, catalytically active dimeric form of nNOS is significantly decreased (~40% decrease in dimer/monomer ratio) with a concurrent increase in PIN expression (~50%), a protein that uncouples dimeric nNOS to monomers and facilitate its degradation. Dimerization of nNOS also requires tetrahydrobiopterin (BH4) for stability and activity. Previously, we have shown that ExT improve NO-mediated sympathetic inhibition in the PVN, however, the molecular mechanism remains elusive. We hypothesized; ExT restores the sympathetic drive by reinstating the levels and catalytically active form of nNOS by abrogating changes in PIN in the PVN of CHF rats.
Methods and Results: 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 reinstated 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 dimers. Interestingly, CHF induced decrease in GCH1 expression was ameliorated with ExT (0.48±0.02 CHF vs 0.70±0.07* ExT-CHF).
Conclusions: Our findings revealed that ExT- rectified, decreased PIN and GCH1 expression and improved dimer/monomer ratio of nNOS in the PVN, which may lead to increase NO resulting in amelioration of activated sympathetic drive during CHF.
Acknowledgements: AHA- 14SDG19980007 and NIH-HL62222 grants.
Author Disclosures: N.M. Sharma: None. X. Liu: None. H. Zheng: None. K.P. Patel: None.
- © 2015 by American Heart Association, Inc.