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Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease

BACKGROUND AND PURPOSE: Calcification of heart valves is a frequent pathological finding in chronic kidney disease and in elderly patients. Hydrogen sulfide (H(2)S) may exert anti‐calcific actions. Here we investigated H(2)S as an inhibitor of valvular calcification and to identify its targets in th...

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Autores principales: Sikura, Katalin Éva, Potor, László, Szerafin, Tamás, Oros, Melinda, Nagy, Péter, Méhes, Gábor, Hendrik, Zoltán, Zarjou, Abolfazl, Agarwal, Anupam, Posta, Niké, Torregrossa, Roberta, Whiteman, Matthew, Fürtös, Ibolya, Balla, György, Balla, József
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024713/
https://www.ncbi.nlm.nih.gov/pubmed/31017307
http://dx.doi.org/10.1111/bph.14691
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author Sikura, Katalin Éva
Potor, László
Szerafin, Tamás
Oros, Melinda
Nagy, Péter
Méhes, Gábor
Hendrik, Zoltán
Zarjou, Abolfazl
Agarwal, Anupam
Posta, Niké
Torregrossa, Roberta
Whiteman, Matthew
Fürtös, Ibolya
Balla, György
Balla, József
author_facet Sikura, Katalin Éva
Potor, László
Szerafin, Tamás
Oros, Melinda
Nagy, Péter
Méhes, Gábor
Hendrik, Zoltán
Zarjou, Abolfazl
Agarwal, Anupam
Posta, Niké
Torregrossa, Roberta
Whiteman, Matthew
Fürtös, Ibolya
Balla, György
Balla, József
author_sort Sikura, Katalin Éva
collection PubMed
description BACKGROUND AND PURPOSE: Calcification of heart valves is a frequent pathological finding in chronic kidney disease and in elderly patients. Hydrogen sulfide (H(2)S) may exert anti‐calcific actions. Here we investigated H(2)S as an inhibitor of valvular calcification and to identify its targets in the pathogenesis. EXPERIMENTAL APPROACH: Effects of H(2)S on osteoblastic transdifferentiation of valvular interstitial cells (VIC) isolated from samples of human aortic valves were studied using immunohistochemistry and western blots. We also assessed H2S on valvular calcification in apolipoprotein E‐deficient (ApoE(−/−)) mice. KEY RESULTS: In human VIC, H(2)S from donor compounds (NaSH, Na(2)S, GYY4137, AP67, and AP72) inhibited mineralization/osteoblastic transdifferentiation, dose‐dependently in response to phosphate. Accumulation of calcium in the extracellular matrix and expression of osteocalcin and alkaline phosphatase was also inhibited. RUNX2 was not translocated to the nucleus and phosphate uptake was decreased. Pyrophosphate generation was increased via up‐regulating ENPP2 and ANK1. Lowering endogenous production of H(2)S by concomitant silencing of cystathionine γ‐lyase (CSE) and cystathionine β‐synthase (CBS) favoured VIC calcification. analysis of human specimens revealed higher Expression of CSE in aorta stenosis valves with calcification (AS) was higher than in valves of aortic insufficiency (AI). In contrast, tissue H(2)S generation was lower in AS valves compared to AI valves. Valvular calcification in ApoE(−/−) mice on a high‐fat diet was inhibited by H(2)S. CONCLUSIONS AND IMPLICATIONS: The endogenous CSE‐CBS/H(2)S system exerts anti‐calcification effects in heart valves providing a novel therapeutic approach to prevent hardening of valves. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc
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spelling pubmed-70247132020-02-21 Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease Sikura, Katalin Éva Potor, László Szerafin, Tamás Oros, Melinda Nagy, Péter Méhes, Gábor Hendrik, Zoltán Zarjou, Abolfazl Agarwal, Anupam Posta, Niké Torregrossa, Roberta Whiteman, Matthew Fürtös, Ibolya Balla, György Balla, József Br J Pharmacol Themed Section: Research Papers BACKGROUND AND PURPOSE: Calcification of heart valves is a frequent pathological finding in chronic kidney disease and in elderly patients. Hydrogen sulfide (H(2)S) may exert anti‐calcific actions. Here we investigated H(2)S as an inhibitor of valvular calcification and to identify its targets in the pathogenesis. EXPERIMENTAL APPROACH: Effects of H(2)S on osteoblastic transdifferentiation of valvular interstitial cells (VIC) isolated from samples of human aortic valves were studied using immunohistochemistry and western blots. We also assessed H2S on valvular calcification in apolipoprotein E‐deficient (ApoE(−/−)) mice. KEY RESULTS: In human VIC, H(2)S from donor compounds (NaSH, Na(2)S, GYY4137, AP67, and AP72) inhibited mineralization/osteoblastic transdifferentiation, dose‐dependently in response to phosphate. Accumulation of calcium in the extracellular matrix and expression of osteocalcin and alkaline phosphatase was also inhibited. RUNX2 was not translocated to the nucleus and phosphate uptake was decreased. Pyrophosphate generation was increased via up‐regulating ENPP2 and ANK1. Lowering endogenous production of H(2)S by concomitant silencing of cystathionine γ‐lyase (CSE) and cystathionine β‐synthase (CBS) favoured VIC calcification. analysis of human specimens revealed higher Expression of CSE in aorta stenosis valves with calcification (AS) was higher than in valves of aortic insufficiency (AI). In contrast, tissue H(2)S generation was lower in AS valves compared to AI valves. Valvular calcification in ApoE(−/−) mice on a high‐fat diet was inhibited by H(2)S. CONCLUSIONS AND IMPLICATIONS: The endogenous CSE‐CBS/H(2)S system exerts anti‐calcification effects in heart valves providing a novel therapeutic approach to prevent hardening of valves. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc John Wiley and Sons Inc. 2019-04-24 2020-02 /pmc/articles/PMC7024713/ /pubmed/31017307 http://dx.doi.org/10.1111/bph.14691 Text en © 2019 University of Debrecen Faculty of medicine. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Themed Section: Research Papers
Sikura, Katalin Éva
Potor, László
Szerafin, Tamás
Oros, Melinda
Nagy, Péter
Méhes, Gábor
Hendrik, Zoltán
Zarjou, Abolfazl
Agarwal, Anupam
Posta, Niké
Torregrossa, Roberta
Whiteman, Matthew
Fürtös, Ibolya
Balla, György
Balla, József
Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease
title Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease
title_full Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease
title_fullStr Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease
title_full_unstemmed Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease
title_short Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease
title_sort hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease
topic Themed Section: Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024713/
https://www.ncbi.nlm.nih.gov/pubmed/31017307
http://dx.doi.org/10.1111/bph.14691
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