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Negative inotropic mechanisms of β-cardiotoxin in cardiomyocytes by depression of myofilament ATPase activity without activation of the classical β-adrenergic pathway
Beta-cardiotoxin (β-CTX) from the king cobra venom (Ophiophagus hannah) was previously proposed as a novel β-adrenergic blocker. However, the involvement of β-adrenergic signaling by this compound has never been elucidated. The objectives of this study were to investigate the underlying mechanisms o...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551325/ https://www.ncbi.nlm.nih.gov/pubmed/34707114 http://dx.doi.org/10.1038/s41598-021-00282-x |
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author | Lertwanakarn, Tuchakorn Suntravat, Montamas Sánchez, Elda E. Wolska, Beata M. Solaro, R. John de Tombe, Pieter P. Tachampa, Kittipong |
author_facet | Lertwanakarn, Tuchakorn Suntravat, Montamas Sánchez, Elda E. Wolska, Beata M. Solaro, R. John de Tombe, Pieter P. Tachampa, Kittipong |
author_sort | Lertwanakarn, Tuchakorn |
collection | PubMed |
description | Beta-cardiotoxin (β-CTX) from the king cobra venom (Ophiophagus hannah) was previously proposed as a novel β-adrenergic blocker. However, the involvement of β-adrenergic signaling by this compound has never been elucidated. The objectives of this study were to investigate the underlying mechanisms of β-CTX as a β-blocker and its association with the β-adrenergic pathway. The effects of β-CTX on isolated cardiac myocyte functions, calcium homeostasis, the phosphorylation level of targeted proteins, and the myofibrillar ATPase activity were studied. Healthy Sprague Dawley rats were used for cardiomyocytes isolation. Like propranolol, β-CTX attenuated the cardiomyocyte inotropy and calcium transient alterations as induced by isoproterenol stimulation. In contrast, these effects were not observed in forskolin-treated cells. Interestingly, cardiomyocytes treated with β-CTX showed no changes in phosphorylation level at any PKA-targeted sites in the myofilaments as demonstrated in Western blot analysis. The skinned fibers study revealed no change in myofilament kinetics by β-CTX. However, this protein exhibited the direct inhibition of myofibrillar ATPase activity with calcium de-sensitization of the enzyme. In summary, the negative inotropic mechanism of β-CTX was discovered. β-CTX exhibits an atypical β-blocker mechanism. These properties of β-CTX may benefit in developing a novel agent aid to treat hypertrophic cardiomyopathy. |
format | Online Article Text |
id | pubmed-8551325 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85513252021-11-01 Negative inotropic mechanisms of β-cardiotoxin in cardiomyocytes by depression of myofilament ATPase activity without activation of the classical β-adrenergic pathway Lertwanakarn, Tuchakorn Suntravat, Montamas Sánchez, Elda E. Wolska, Beata M. Solaro, R. John de Tombe, Pieter P. Tachampa, Kittipong Sci Rep Article Beta-cardiotoxin (β-CTX) from the king cobra venom (Ophiophagus hannah) was previously proposed as a novel β-adrenergic blocker. However, the involvement of β-adrenergic signaling by this compound has never been elucidated. The objectives of this study were to investigate the underlying mechanisms of β-CTX as a β-blocker and its association with the β-adrenergic pathway. The effects of β-CTX on isolated cardiac myocyte functions, calcium homeostasis, the phosphorylation level of targeted proteins, and the myofibrillar ATPase activity were studied. Healthy Sprague Dawley rats were used for cardiomyocytes isolation. Like propranolol, β-CTX attenuated the cardiomyocyte inotropy and calcium transient alterations as induced by isoproterenol stimulation. In contrast, these effects were not observed in forskolin-treated cells. Interestingly, cardiomyocytes treated with β-CTX showed no changes in phosphorylation level at any PKA-targeted sites in the myofilaments as demonstrated in Western blot analysis. The skinned fibers study revealed no change in myofilament kinetics by β-CTX. However, this protein exhibited the direct inhibition of myofibrillar ATPase activity with calcium de-sensitization of the enzyme. In summary, the negative inotropic mechanism of β-CTX was discovered. β-CTX exhibits an atypical β-blocker mechanism. These properties of β-CTX may benefit in developing a novel agent aid to treat hypertrophic cardiomyopathy. Nature Publishing Group UK 2021-10-27 /pmc/articles/PMC8551325/ /pubmed/34707114 http://dx.doi.org/10.1038/s41598-021-00282-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lertwanakarn, Tuchakorn Suntravat, Montamas Sánchez, Elda E. Wolska, Beata M. Solaro, R. John de Tombe, Pieter P. Tachampa, Kittipong Negative inotropic mechanisms of β-cardiotoxin in cardiomyocytes by depression of myofilament ATPase activity without activation of the classical β-adrenergic pathway |
title | Negative inotropic mechanisms of β-cardiotoxin in cardiomyocytes by depression of myofilament ATPase activity without activation of the classical β-adrenergic pathway |
title_full | Negative inotropic mechanisms of β-cardiotoxin in cardiomyocytes by depression of myofilament ATPase activity without activation of the classical β-adrenergic pathway |
title_fullStr | Negative inotropic mechanisms of β-cardiotoxin in cardiomyocytes by depression of myofilament ATPase activity without activation of the classical β-adrenergic pathway |
title_full_unstemmed | Negative inotropic mechanisms of β-cardiotoxin in cardiomyocytes by depression of myofilament ATPase activity without activation of the classical β-adrenergic pathway |
title_short | Negative inotropic mechanisms of β-cardiotoxin in cardiomyocytes by depression of myofilament ATPase activity without activation of the classical β-adrenergic pathway |
title_sort | negative inotropic mechanisms of β-cardiotoxin in cardiomyocytes by depression of myofilament atpase activity without activation of the classical β-adrenergic pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551325/ https://www.ncbi.nlm.nih.gov/pubmed/34707114 http://dx.doi.org/10.1038/s41598-021-00282-x |
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