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001-es BibID:BIBFORM078538
035-os BibID:(WoS)000513525100008 (Scopus)85067838371
Első szerző:Sikura Katalin Éva (biológus)
Cím: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
Dátum:2020
ISSN:0007-1188
Megjegyzések:BACKGROUND AND PURPOSE: Calcification of heart valves is a frequent pathological finding in CKD patients and in elderly. Hydrogen sulfide (H2 S) has been suggested to possess various anti-calcific actions. We aimed to investigate H2 S as a potential therapeutic in valvular calcification and to identify its targets in the pathogenesis. EXPERIMENTAL APPROACH: Potential of H2 S for regulating osteoblastic transdifferentiation of valvular interstitial cells (VIC) isolated from human aortic valves were studied and tested for valvular calcification in apolipoprotein E-deficient mice (ApoE-/- ). KEY RESULTS: In human VIC H2 S treatment employing donors (NaSH, Na2 S, GYY4137, AP67, AP72) inhibited mineralization/osteoblastic transdifferentiation in a dose-responsive manner in response to phosphate. Accumulation of calcium in the extracellular matrix and expression of osteocalcin and alkaline phosphatase was abrogated. Nuclear translocation of the RUNX2 did not occur, and phosphate uptake was lowered. We also found that pyrophosphate generation was increased via up-regulating ENPP2 and ANK1. Lowering endogenous production of H2 S by concomitant silencing of CSE and CBS favored VIC calcification. IHC and Western blot analysis of human specimens revealed higher levels of CSE expression in aorta stenosis valves with calcification (AS) compared to valves of aorta insufficiency (AI). In contrast, tissue H2 S generation was lower in AS valves compared to AI valves. We observed an inhibition of valvular calcification by H2 S in ApoE-/- mouse on high-fat diet. CONCLUSION AND IMPLICATIONS: Our study suggests that the CSE-CBS/H2 S system exhibits an anti-calcification function in heart valves providing a novel therapeutic approach to prevent hardening of valves. This article is protected by copyright. All rights reserved. KEYWORDS: AP67; AP72; GYY4137; H2S; aortic valve; apolipoprotein E knockout mice; calcification; pyrophosphate
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
hydrogen sulphide
valvular calcification
Megjelenés:British Journal of Pharmacology. - 177 : 4 (2020), p. 793-809. -
További szerzők:Potor László Szerafin Tamás (1960-) (szívsebész, mellkassebész) Oros Melinda (1975-) (molekuláris biológus) Nagy Péter (1976-) (vegyész) Méhes Gábor (1966-) (patológus) Hendrik Zoltán (1986-) (orvos) Zarjou, Abolfazl (1979-) (kutató orvos) Agarwal, Anupam Posta Niké Torregrossa, Roberta Whiteman, Matthew Fürtös Ibolya Balla György (1953-) (csecsemő és gyermekgyógyász, neonatológus) Balla József (1959-) (belgyógyász, nephrológus)
Pályázati támogatás:GINOP-2.3.2-15-2016-00043
GINOP
EFOP-3.6.2-16-2017-00006
EFOP
OTKA-112333
OTKA
11003
MTA
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2.

001-es BibID:BIBFORM076938
035-os BibID:(WoS)000460459200017 (Scopus)85062410676
Első szerző:Sikura Katalin Éva (biológus)
Cím:Potential Role of H-Ferritin in Mitigating Valvular Mineralization / Katalin Éva Sikura, László Potor, Tamás Szerafin, Abolfazl Zarjou, Anupam Agarwal, Paolo Arosio, Maura Poli, Zoltán Hendrik, Gábor Méhes, Melinda Oros, Niké Posta, Lívia Beke, Ibolya Fürtös, György Balla, József Balla
Dátum:2019
ISSN:1079-5642
Megjegyzések:Objective- Calcific aortic valve disease is a prominent finding in elderly and in patients with chronic kidney disease. We investigated the potential role of iron metabolism in the pathogenesis of calcific aortic valve disease. Approach and Results- Cultured valvular interstitial cells of stenotic aortic valve with calcification from patients undergoing valve replacement exhibited significant susceptibility to mineralization/osteoblastic transdifferentiation in response to phosphate. This process was abrogated by iron via induction of H-ferritin as reflected by lowering ALP and osteocalcin secretion and preventing extracellular calcium deposition. Cellular phosphate uptake and accumulation of lysosomal phosphate were decreased. Accordingly, expression of phosphate transporters Pit1 and Pit2 were repressed. Translocation of ferritin into lysosomes occurred with high phosphate-binding capacity. Importantly, ferritin reduced nuclear accumulation of RUNX2 (Runt-related transcription factor 2), and as a reciprocal effect, it enhanced nuclear localization of transcription factor Sox9 (SRY [sex-determining region Y]-box 9). Pyrophosphate generation was also increased via upregulation of ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase-2). 3H-1, 2-dithiole-3-thione mimicked these beneficial effects in valvular interstitial cell via induction of H-ferritin. Ferroxidase activity of H-ferritin was essential for this function, as ceruloplasmin exhibited similar inhibitory functions. Histological analysis of stenotic aortic valve revealed high expression of H-ferritin without iron accumulation and its relative dominance over ALP in noncalcified regions. Increased expression of H-ferritin accompanied by elevation of TNF-α (tumor necrosis factor-α) and IL-1β (interleukin-1β) levels, inducers of H-ferritin, corroborates the essential role of ferritin/ferroxidase via attenuating inflammation in calcific aortic valve disease. Conclusions- Our results indicate that H-ferritin is a stratagem in mitigating valvular mineralization/osteoblastic differentiation. Utilization of 3H-1, 2-dithiole-3-thione to induce ferritin expression may prove a novel therapeutic potential in valvular mineralization.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
arteriosclerosis
chronic kidney disease
phosphate
stenosis
vascular calcification
Megjelenés:Arteriosclerosis Thrombosis and Vascular Biology. - 39 : 3 (2019), p. 413-431. -
További szerzők:Potor László Szerafin Tamás (1960-) (szívsebész, mellkassebész) Zarjou, Abolfazl (1979-) (kutató orvos) Agarwal, Anupam Arosio, Paolo Poli, Maura Hendrik Zoltán (1986-) (orvos) Méhes Gábor (1966-) (patológus) Oros Melinda (1975-) (molekuláris biológus) Posta Niké Beke Lívia Fürtös Ibolya Balla György (1953-) (csecsemő és gyermekgyógyász, neonatológus) Balla József (1959-) (belgyógyász, nephrológus)
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