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

ABSTRACT: BACKGROUND AND PURPOSE:Calcification of heart valves is a frequent pathological finding in chronic kidney disease and in elderly patients. Hydrogen sulfide (H2 S) may exert anti-calcific actions. Here we investigated H2 S as an inhibitor of valvular calcification and to identify its targets in the pathogenesis. EXPERIMENTAL APPROACH:Effects of H2 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, H2 S from donor compounds (NaSH, Na2 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 H2 S by concomitant silencing of cystathionine ?-lyase (CSE) and cystathionine ?-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 H2 S generation was lower in AS valves compared to AI valves. Valvular calcification in ApoE-/- mice on a high-fat diet was inhibited by H2 S. CONCLUSIONS AND IMPLICATIONS:The endogenous CSE-CBS/H2 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.

SUBMITTER: Sikura KE

PROVIDER: S-EPMC7024713 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Sikura Katalin Éva KÉ Potor László L Szerafin Tamás T Oros Melinda M Nagy Péter P Méhes Gábor G Hendrik Zoltán Z Zarjou Abolfazl A Agarwal Anupam A Posta Niké N Torregrossa Roberta R Whiteman Matthew M Fürtös Ibolya I Balla György G Balla József J

British journal of pharmacology 20190424 4

<h4>Background and purpose</h4>Calcification of heart valves is a frequent pathological finding in chronic kidney disease and in elderly patients. Hydrogen sulfide (H<sub>2</sub> S) may exert anti-calcific actions. Here we investigated H<sub>2</sub> S as an inhibitor of valvular calcification and to identify its targets in the pathogenesis.<h4>Experimental approach</h4>Effects of H<sub>2</sub> S on osteoblastic transdifferentiation of valvular interstitial cells (VIC) isolated from samples of hu ...[more]

PMID: 31017307

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Project description:Hydrogen sulfide (H2S) was previously revealed to inhibit osteoblastic differentiation of valvular interstitial cells (VICs), a pathological feature in calcific aortic valve disease (CAVD). This study aimed to explore the metabolic control of H2S levels in human aortic valves. Lower levels of bioavailable H2S and higher levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were detected in aortic valves of CAVD patients compared to healthy individuals, accompanied by higher expression of cystathionine γ-lyase (CSE) and same expression of cystathionine β-synthase (CBS). Increased biogenesis of H2S by CSE was found in the aortic valves of CAVD patients which is supported by increased production of lanthionine. In accordance, healthy human aortic VICs mimic human pathology under calcifying conditions, as elevated CSE expression is associated with low levels of H2S. The expression of mitochondrial enzymes involved in H2S catabolism including sulfide quinone oxidoreductase (SQR), the key enzyme in mitochondrial H2S oxidation, persulfide dioxygenase (ETHE1), sulfite oxidase (SO) and thiosulfate sulfurtransferase (TST) were up-regulated in calcific aortic valve tissues, and a similar expression pattern was observed in response to high phosphate levels in VICs. AP39, a mitochondria-targeting H2S donor, rescued VICs from an osteoblastic phenotype switch and reduced the expression of IL-1β and TNF-α in VICs. Both pro-inflammatory cytokines aggravated calcification and osteoblastic differentiation of VICs derived from the calcific aortic valves. In contrast, IL-1β and TNF-α provided an early and transient inhibition of VICs calcification and osteoblastic differentiation in healthy cells and that effect was lost as H2S levels decreased. The benefit was mediated via CSE induction and H2S generation. We conclude that decreased levels of bioavailable H2S in human calcific aortic valves result from an increased H2S metabolism that facilitates the development of CAVD. CSE/H2S represent a pathway that reverses the action of calcifying stimuli.

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

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

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