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

Katalin Éva Sikura, László Potor, Tamás Szerafin, Melinda Oros, Péter Nagy, Gábor Méhes, Zoltán Hendrik, Abolfazl Zarjou, Anupam Agarwal, Niké Posta, Roberta Torregrossa, Matthew Whiteman, Ibolya Fürtös, György Balla, József Balla

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Background and Purpose: Calcification of heart valves is a frequent pathological finding in chronic kidney disease and in elderly patients. Hydrogen sulfide (H2S) may exert anti-calcific actions. Here we investigated H2S as an inhibitor of valvular calcification and to identify its targets in the pathogenesis. Experimental Approach: Effects of H2S 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, H2S from donor compounds (NaSH, Na2S, 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 H2S 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 H2S generation was lower in AS valves compared to AI valves. Valvular calcification in ApoE−/− mice on a high-fat diet was inhibited by H2S. Conclusions and Implications: The endogenous CSE-CBS/H2S 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.

Original languageEnglish
Pages (from-to)793-809
Number of pages17
JournalBritish journal of pharmacology
Issue number4
Publication statusPublished - Feb 1 2020

ASJC Scopus subject areas

  • Pharmacology

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    Sikura, K. É., Potor, L., Szerafin, T., Oros, M., Nagy, P., Méhes, G., Hendrik, Z., Zarjou, A., Agarwal, A., Posta, N., Torregrossa, R., Whiteman, M., Fürtös, I., Balla, G., & Balla, J. (2020). Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease. British journal of pharmacology, 177(4), 793-809. https://doi.org/10.1111/bph.14691