Obligatory role of neuronal nitric oxide synthase in the heart's antioxidant adaptation with exercise

Steve R. Roof, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Hsiang-Ting Ho, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Sean C. Little, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.Follow
Joseph E. Ostler, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Elizabeth A. Brundage, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Muthu Periasamy, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Frederick A. Villamena, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Sandor Györke, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Brandon J. Biesiadecki, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Christophe Heymes, Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, Toulouse, France.
Steven R. Houser, Department of Physiology, Cardiovascular Research Center, Temple University, Philadelphia, PA, USA.
Jonathan P. Davis, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Mark T. Ziolo, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA. Electronic address: ziolo.1@osu.edu.

Document Type

Article

Abstract

Excessive oxidative stress in the heart results in contractile dysfunction. While antioxidant therapies have been a disappointment clinically, exercise has shown beneficial results, in part by reducing oxidative stress. We have previously shown that neuronal nitric oxide synthase (nNOS) is essential for cardioprotective adaptations caused by exercise. We hypothesize that part of the cardioprotective role of nNOS is via the augmentation of the antioxidant defense with exercise by positively shifting the nitroso-redox balance. Our results show that nNOS is indispensable for the augmented anti-oxidant defense with exercise. Furthermore, exercise training of nNOS knockout mice resulted in a negative shift in the nitroso-redox balance resulting in contractile dysfunction. Remarkably, overexpressing nNOS (conditional cardiac-specific nNOS overexpression) was able to mimic exercise by increasing VO2max. This study demonstrates that exercise results in a positive shift in the nitroso-redox balance that is nNOS-dependent. Thus, targeting nNOS signaling may mimic the beneficial effects of exercise by combating oxidative stress and may be a viable treatment strategy for heart disease.

Medical Subject Headings

Adaptation, Physiological; Animals; Calcium (metabolism); Calcium-Binding Proteins (genetics, metabolism); Gene Expression Regulation; Mice; Mice, Knockout; Myocardial Contraction (physiology); Myocardium (cytology, metabolism); Myocytes, Cardiac (cytology, metabolism); Nitric Oxide (biosynthesis); Nitric Oxide Synthase Type I (deficiency, genetics); Oxidation-Reduction; Oxidative Stress; Physical Conditioning, Animal; Primary Cell Culture; Reactive Nitrogen Species (metabolism); Reactive Oxygen Species (metabolism); Signal Transduction

Publication Date

4-1-2015

Publication Title

Journal of molecular and cellular cardiology

E-ISSN

1095-8584

Volume

81

First Page

54

Last Page

61

PubMed ID

25595735

Digital Object Identifier (DOI)

10.1016/j.yjmcc.2015.01.003

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