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Exercise training augments neuronal nitric oxide synthase dimerization in the paraventricular nucleus of rats with chronic heart failure.
Nitric Oxide. 2019 06 01; 87:73-82.NO

Abstract

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.

Authors+Show Affiliations

Department of Cellular and Integrative Physiology, UNMC, Omaha, NE 68198-5850, USA. Electronic address: nsharma@unmc.edu.Department of Cellular and Integrative Physiology, UNMC, Omaha, NE 68198-5850, USA.Department of Cellular and Integrative Physiology, UNMC, Omaha, NE 68198-5850, USA.Department of Cellular and Integrative Physiology, UNMC, Omaha, NE 68198-5850, USA.Department of Cellular and Integrative Physiology, UNMC, Omaha, NE 68198-5850, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30878404

Citation

Sharma, Neeru M., et al. "Exercise Training Augments Neuronal Nitric Oxide Synthase Dimerization in the Paraventricular Nucleus of Rats With Chronic Heart Failure." Nitric Oxide : Biology and Chemistry, vol. 87, 2019, pp. 73-82.
Sharma NM, Liu X, Llewellyn TL, et al. Exercise training augments neuronal nitric oxide synthase dimerization in the paraventricular nucleus of rats with chronic heart failure. Nitric Oxide. 2019;87:73-82.
Sharma, N. M., Liu, X., Llewellyn, T. L., Katsurada, K., & Patel, K. P. (2019). Exercise training augments neuronal nitric oxide synthase dimerization in the paraventricular nucleus of rats with chronic heart failure. Nitric Oxide : Biology and Chemistry, 87, 73-82. https://doi.org/10.1016/j.niox.2019.03.005
Sharma NM, et al. Exercise Training Augments Neuronal Nitric Oxide Synthase Dimerization in the Paraventricular Nucleus of Rats With Chronic Heart Failure. Nitric Oxide. 2019 06 1;87:73-82. PubMed PMID: 30878404.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exercise training augments neuronal nitric oxide synthase dimerization in the paraventricular nucleus of rats with chronic heart failure. AU - Sharma,Neeru M, AU - Liu,Xuefei, AU - Llewellyn,Tamra L, AU - Katsurada,Kenichi, AU - Patel,Kaushik P, Y1 - 2019/03/13/ PY - 2018/07/17/received PY - 2019/02/06/revised PY - 2019/03/08/accepted PY - 2020/06/01/pmc-release PY - 2019/3/18/pubmed PY - 2019/12/4/medline PY - 2019/3/18/entrez KW - BH4 KW - Exercise training KW - PIN KW - Paraventricular nucleus KW - nNOS SP - 73 EP - 82 JF - Nitric oxide : biology and chemistry JO - Nitric Oxide VL - 87 N2 - 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. SN - 1089-8611 UR - https://www.unboundmedicine.com/medline/citation/30878404/Exercise_training_augments_neuronal_nitric_oxide_synthase_dimerization_in_the_paraventricular_nucleus_of_rats_with_chronic_heart_failure_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1089-8603(18)30197-6 DB - PRIME DP - Unbound Medicine ER -