Nitric oxide down-regulates voltage-gated Na <sup>+</sup> channel in cardiomyocytes possibly through S-nitrosylation-mediated signaling

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Abstract

Nitric oxide (NO) is produced from endothelial cells and cardiomyocytes composing the myocardium and benefits cardiac function through both vascular-dependent and—independent effects. This study was purposed to investigate the possible adverse effect of NO focusing on the voltage-gated Na ⁺ channel in cardiomyocytes. We carried out patch-clamp experiments on rat neonatal cardiomyocytes demonstrating that NOC-18, an NO donor, significantly reduced Na ⁺ channel current in a dose-dependent manner by a long-term application for 24 h, accompanied by a reduction of Nav1.5-mRNA and the protein, and an increase of a transcription factor forkhead box protein O1 (FOXO1) in the nucleus. The effect of NOC-18 on the Na ⁺ channel was blocked by an inhibitor of thiol oxidation N-ethylmaleimide, a disulfide reducing agent disulfide 1,4-Dithioerythritol, or a FOXO1 activator paclitaxel, suggesting that NO is a negative regulator of the voltage-gated Na ⁺ channel through thiols in regulatory protein(s) for the channel transcription.

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Nitric oxide (NO) is produced from virtually all cell types composing the myocardium and regulates cardiac function through both vascular-dependent and -independent effects. The former include regulation of coronary vessel tone, thrombogenicity, and proliferative and inflammatory properties as well as cellular cross-talk supporting angiogenesis. The latter comprise the direct effects of NO on several aspects of cardiomyocyte contractility, from the fine regulation of excitation-contraction coupling to modulation of (presynaptic and postsynaptic) autonomic signaling and mitochondrial respiration. This multifaceted involvement of NO in cardiac physiology is supported by a tight molecular regulation of the three NO synthases, from cellular spatial confinement to posttranslational allosteric modulation by specific interacting proteins, acting in concert to restrict the influence of NO to a particular intracellular target in a stimulus-specific manner. Loss of this specificity, such as produced on excessive NO delivery from inflammatory cells (or cytokine-stimulated cardiomyocytes themselves), may result in profound cellular disturbances leading to heart failure. Future therapeutic manipulations of cardiac NO synthesis will necessarily draw on additional characterization of the cellular and molecular determinants for the net effect of this versatile radical on the cardiomyocyte biology.

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Ischaemic heart disease is one of the leading causes of morbidity and mortality worldwide. The development of cardioprotective therapeutic agents remains a partly unmet need and a challenge for both medicine and industry, with significant financial and social implications. Protection of the myocardium can be achieved by mechanical vascular occlusions such as preconditioning (PC), when brief episodes of ischaemia/reperfusion (I/R) are experienced prior to ischaemia; postconditioning (PostC), when the brief episodes are experienced at the immediate onset of reperfusion; and remote conditioning (RC), when the brief episodes are experienced in another vascular territory. The elucidation of the signalling pathways, which underlie the protective effects of PC, PostC and RC, would be expected to reveal novel molecular targets for cardioprotection that could be modulated by pharmacological agents to prevent reperfusion injury. Gasotransmitters including NO, hydrogen sulphide (H2S) and carbon monoxide (CO) are a growing family of regulatory molecules that affect physiological and pathological functions. NO, H2S and CO share several common properties; they are beneficial at low concentrations but hazardous in higher amounts; they relax smooth muscle cells, inhibit apoptosis and exert anti-inflammatory effects. In the cardiovascular system, NO, H2S and CO induce vasorelaxation and promote cardioprotection. In this review article, we summarize current knowledge on the role of the gasotransmitters NO, H2S and CO in myocardial I/R injury and cardioprotection provided by conditioning strategies and highlight future perspectives in cardioprotection by NO, H2S, CO, as well as their donor molecules. © 2014 The British Pharmacological Society.

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Ricardo Carnicer, Mark Crabtree, Vidhya Sivakumaran … (2013)

The regulation of myocardial function by constitutive nitric oxide synthases (NOS) is important for the maintenance of myocardial Ca(2+) homeostasis, relaxation and distensibility, and protection from arrhythmia and abnormal stress stimuli. However, sustained insults such as diabetes, hypertension, hemodynamic overload, and atrial fibrillation lead to dysfunctional NOS activity with superoxide produced instead of NO and worse pathophysiology. Major strides in understanding the role of normal and abnormal constitutive NOS in the heart have revealed molecular targets by which NO modulates myocyte function and morphology, the role and nature of post-translational modifications of NOS, and factors controlling nitroso-redox balance. Localized and differential signaling from NOS1 (neuronal) versus NOS3 (endothelial) isoforms are being identified, as are methods to restore NOS function in heart disease. Abnormal NOS signaling plays a key role in many cardiac disorders, while targeted modulation may potentially reverse this pathogenic source of oxidative stress. Improvements in the clinical translation of potent modulators of NOS function/dysfunction may ultimately provide a powerful new treatment for many hearts diseases that are fueled by nitroso-redox imbalance.

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Author and article information

Contributors

Katsushige Ono: ono@oita-u.ac.jp

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 28 May 2021

Publication date PMC-release: 28 May 2021

Publication date Collection: 2021

Volume: 11

Electronic Location Identifier: 11273

Affiliations

[1 ]GRID grid.452458.a, Department of Cardiology, , The First Hospital of Hebei Medical University, ; 89 Donggang Road, Shijiazhuang, 050031 Hebei Province People’s Republic of China

[2 ]GRID grid.258622.9, ISNI 0000 0004 1936 9967, Department of Food Science and Nutrition, Faculty of Agriculture, , Kindai University, ; Nara, Japan

[3 ]GRID grid.412334.3, ISNI 0000 0001 0665 3553, Department of Pathophysiology, , Oita University School of Medicine, ; Yufu, Oita 879-5593 Japan

Article

Publisher ID: 90840

DOI: 10.1038/s41598-021-90840-0

PMC ID: 8163867

PubMed ID: 34050231

SO-VID: 888ca755-6f63-4b02-93cd-d1ee8fb66e97

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 26 January 2021

Date accepted : 18 May 2021

Funding

Funded by: JSPS KAKEN

Award ID: 25460292

Award Recipient : Katsushige Ono

Custom metadata

ScienceOpen disciplines: Uncategorized

Keywords: physiology,cardiology

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ScienceOpen disciplines: Uncategorized

Keywords: physiology, cardiology

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