Cargando…

CTH/MPST double ablation results in enhanced vasorelaxation and reduced blood pressure via upregulation of the eNOS/sGC pathway

Hydrogen sulfide (H(2)S), a gasotransmitter with protective effects in the cardiovascular system, is endogenously generated by three main enzymatic pathways: cystathionine gamma lyase (CTH), cystathionine beta synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST) enzymes. CTH and MPST are t...

Descripción completa

Detalles Bibliográficos
Autores principales: Katsouda, Antonia, Markou, Maria, Zampas, Paraskevas, Varela, Aimilia, Davos, Constantinos H., Vellecco, Valentina, Cirino, Giuseppe, Bucci, Mariarosaria, Papapetropoulos, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9969096/
https://www.ncbi.nlm.nih.gov/pubmed/36860295
http://dx.doi.org/10.3389/fphar.2023.1090654
_version_ 1784897647857893376
author Katsouda, Antonia
Markou, Maria
Zampas, Paraskevas
Varela, Aimilia
Davos, Constantinos H.
Vellecco, Valentina
Cirino, Giuseppe
Bucci, Mariarosaria
Papapetropoulos, Andreas
author_facet Katsouda, Antonia
Markou, Maria
Zampas, Paraskevas
Varela, Aimilia
Davos, Constantinos H.
Vellecco, Valentina
Cirino, Giuseppe
Bucci, Mariarosaria
Papapetropoulos, Andreas
author_sort Katsouda, Antonia
collection PubMed
description Hydrogen sulfide (H(2)S), a gasotransmitter with protective effects in the cardiovascular system, is endogenously generated by three main enzymatic pathways: cystathionine gamma lyase (CTH), cystathionine beta synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST) enzymes. CTH and MPST are the predominant sources of H(2)S in the heart and blood vessels, exhibiting distinct effects in the cardiovascular system. To better understand the impact of H(2)S in cardiovascular homeostasis, we generated a double Cth/Mpst knockout (Cth/Mpst ( −/− )) mouse and characterized its cardiovascular phenotype. CTH/MPST-deficient mice were viable, fertile and exhibited no gross abnormalities. Lack of both CTH and MPST did not affect the levels of CBS and H(2)S-degrading enzymes in the heart and the aorta. Cth/Mpst ( −/− ) mice also exhibited reduced systolic, diastolic and mean arterial blood pressure, and presented normal left ventricular structure and fraction. Aortic ring relaxation in response to exogenously applied H(2)S was similar between the two genotypes. Interestingly, an enhanced endothelium-dependent relaxation to acetylcholine was observed in mice in which both enzymes were deleted. This paradoxical change was associated with upregulated levels of endothelial nitric oxide synthase (eNOS) and soluble guanylate cyclase (sGC) α1 and β1 subunits and increased NO-donor-induced vasorelaxation. Administration of a NOS-inhibitor, increased mean arterial blood pressure to a similar extent in wild-type and Cth/Mpst ( −/− ) mice. We conclude that chronic elimination of the two major H(2)S sources in the cardiovascular system, leads to an adaptive upregulation of eNOS/sGC signaling, revealing novel ways through which H(2)S affects the NO/cGMP pathway.
format Online
Article
Text
id pubmed-9969096
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-99690962023-02-28 CTH/MPST double ablation results in enhanced vasorelaxation and reduced blood pressure via upregulation of the eNOS/sGC pathway Katsouda, Antonia Markou, Maria Zampas, Paraskevas Varela, Aimilia Davos, Constantinos H. Vellecco, Valentina Cirino, Giuseppe Bucci, Mariarosaria Papapetropoulos, Andreas Front Pharmacol Pharmacology Hydrogen sulfide (H(2)S), a gasotransmitter with protective effects in the cardiovascular system, is endogenously generated by three main enzymatic pathways: cystathionine gamma lyase (CTH), cystathionine beta synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST) enzymes. CTH and MPST are the predominant sources of H(2)S in the heart and blood vessels, exhibiting distinct effects in the cardiovascular system. To better understand the impact of H(2)S in cardiovascular homeostasis, we generated a double Cth/Mpst knockout (Cth/Mpst ( −/− )) mouse and characterized its cardiovascular phenotype. CTH/MPST-deficient mice were viable, fertile and exhibited no gross abnormalities. Lack of both CTH and MPST did not affect the levels of CBS and H(2)S-degrading enzymes in the heart and the aorta. Cth/Mpst ( −/− ) mice also exhibited reduced systolic, diastolic and mean arterial blood pressure, and presented normal left ventricular structure and fraction. Aortic ring relaxation in response to exogenously applied H(2)S was similar between the two genotypes. Interestingly, an enhanced endothelium-dependent relaxation to acetylcholine was observed in mice in which both enzymes were deleted. This paradoxical change was associated with upregulated levels of endothelial nitric oxide synthase (eNOS) and soluble guanylate cyclase (sGC) α1 and β1 subunits and increased NO-donor-induced vasorelaxation. Administration of a NOS-inhibitor, increased mean arterial blood pressure to a similar extent in wild-type and Cth/Mpst ( −/− ) mice. We conclude that chronic elimination of the two major H(2)S sources in the cardiovascular system, leads to an adaptive upregulation of eNOS/sGC signaling, revealing novel ways through which H(2)S affects the NO/cGMP pathway. Frontiers Media S.A. 2023-02-13 /pmc/articles/PMC9969096/ /pubmed/36860295 http://dx.doi.org/10.3389/fphar.2023.1090654 Text en Copyright © 2023 Katsouda, Markou, Zampas, Varela, Davos, Vellecco, Cirino, Bucci and Papapetropoulos. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Katsouda, Antonia
Markou, Maria
Zampas, Paraskevas
Varela, Aimilia
Davos, Constantinos H.
Vellecco, Valentina
Cirino, Giuseppe
Bucci, Mariarosaria
Papapetropoulos, Andreas
CTH/MPST double ablation results in enhanced vasorelaxation and reduced blood pressure via upregulation of the eNOS/sGC pathway
title CTH/MPST double ablation results in enhanced vasorelaxation and reduced blood pressure via upregulation of the eNOS/sGC pathway
title_full CTH/MPST double ablation results in enhanced vasorelaxation and reduced blood pressure via upregulation of the eNOS/sGC pathway
title_fullStr CTH/MPST double ablation results in enhanced vasorelaxation and reduced blood pressure via upregulation of the eNOS/sGC pathway
title_full_unstemmed CTH/MPST double ablation results in enhanced vasorelaxation and reduced blood pressure via upregulation of the eNOS/sGC pathway
title_short CTH/MPST double ablation results in enhanced vasorelaxation and reduced blood pressure via upregulation of the eNOS/sGC pathway
title_sort cth/mpst double ablation results in enhanced vasorelaxation and reduced blood pressure via upregulation of the enos/sgc pathway
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9969096/
https://www.ncbi.nlm.nih.gov/pubmed/36860295
http://dx.doi.org/10.3389/fphar.2023.1090654
work_keys_str_mv AT katsoudaantonia cthmpstdoubleablationresultsinenhancedvasorelaxationandreducedbloodpressureviaupregulationoftheenossgcpathway
AT markoumaria cthmpstdoubleablationresultsinenhancedvasorelaxationandreducedbloodpressureviaupregulationoftheenossgcpathway
AT zampasparaskevas cthmpstdoubleablationresultsinenhancedvasorelaxationandreducedbloodpressureviaupregulationoftheenossgcpathway
AT varelaaimilia cthmpstdoubleablationresultsinenhancedvasorelaxationandreducedbloodpressureviaupregulationoftheenossgcpathway
AT davosconstantinosh cthmpstdoubleablationresultsinenhancedvasorelaxationandreducedbloodpressureviaupregulationoftheenossgcpathway
AT velleccovalentina cthmpstdoubleablationresultsinenhancedvasorelaxationandreducedbloodpressureviaupregulationoftheenossgcpathway
AT cirinogiuseppe cthmpstdoubleablationresultsinenhancedvasorelaxationandreducedbloodpressureviaupregulationoftheenossgcpathway
AT buccimariarosaria cthmpstdoubleablationresultsinenhancedvasorelaxationandreducedbloodpressureviaupregulationoftheenossgcpathway
AT papapetropoulosandreas cthmpstdoubleablationresultsinenhancedvasorelaxationandreducedbloodpressureviaupregulationoftheenossgcpathway