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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalBritish Journal of Pharmacology
DOIs
Publication statusPublished - Jan 1 2019

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Cystathionine
Aortic Diseases
Hydrogen Sulfide
Heart Valves
Aortic Valve
Lyases
Aortic Valve Insufficiency
Apolipoproteins E
Phosphates
Osteocalcin
High Fat Diet
Chronic Renal Insufficiency
Extracellular Matrix
Alkaline Phosphatase
Aorta
Pathologic Constriction
Western Blotting
Immunohistochemistry
Tissue Donors
Calcium

ASJC Scopus subject areas

  • Pharmacology

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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, G.; Hendrik, Zoltán; Zarjou, Abolfazl; Agarwal, Anupam; Posta, Niké; Torregrossa, Roberta; Whiteman, Matthew; Fürtös, Ibolya; Balla, G.; Balla, J.

In: British Journal of Pharmacology, 01.01.2019.

Research output: Contribution to journalArticle

Sikura, KÉ, 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 2019, 'Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease', British Journal of Pharmacology. https://doi.org/10.1111/bph.14691
Sikura, Katalin Éva ; Potor, László ; Szerafin, Tamás ; Oros, Melinda ; Nagy, Péter ; Méhes, G. ; Hendrik, Zoltán ; Zarjou, Abolfazl ; Agarwal, Anupam ; Posta, Niké ; Torregrossa, Roberta ; Whiteman, Matthew ; Fürtös, Ibolya ; Balla, G. ; Balla, J. / Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease. In: British Journal of Pharmacology. 2019.
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AU - Potor, László

AU - Szerafin, Tamás

AU - Oros, Melinda

AU - Nagy, Péter

AU - Méhes, G.

AU - Hendrik, Zoltán

AU - Zarjou, Abolfazl

AU - Agarwal, Anupam

AU - Posta, Niké

AU - Torregrossa, Roberta

AU - Whiteman, Matthew

AU - Fürtös, Ibolya

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