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001-es BibID:	BIBFORM089749
035-os BibID:	(cikkazonosító)8172 (scopus)85094855183 (wos)000588924400001
Első szerző:	Alvarado, Gerardo
Cím:	Heme-Induced Oxidation of Cysteine Groups of Myofilament Proteins Leads to Contractile Dysfunction of Permeabilized Human Skeletal Muscle Fibres / Alvarado Gerardo, Tóth Attila, Csősz Éva, Kalló Gergő, Dankó Katalin, Csernátony Zoltán, Smith Ann, Gram Magnus, Akerström Bo, Édes István, Balla György, Papp Zoltán, Balla József
Dátum:	2020
ISSN:	1661-6596 1422-0067
Megjegyzések:	Heme released from red blood cells targets a number of cell components including the cytoskeleton. The purpose of the present study was to determine the impact of free heme (20?300 ?M) on human skeletal muscle fibres made available during orthopedic surgery. Isometric force production and oxidative protein modifications were monitored in permeabilized skeletal muscle fibre segments. A single heme exposure (20 ?M) to muscle fibres decreased Ca2+-activated maximal (active) force (Fo) by about 50% and evoked an approximately 3-fold increase in Ca2+-independent (passive) force (Fpassive). Oxidation of sulfhydryl (SH) groups was detected in structural proteins (e.g., nebulin, ?-actinin, meromyosin 2) and in contractile proteins (e.g., myosin heavy chain and myosin-binding protein C) as well as in titin in the presence of 300 ?M heme. This SH oxidation was not reversed by dithiothreitol (50 mM). Sulfenic acid (SOH) formation was also detected in the structural proteins (nebulin, ?-actinin, meromyosin). Heme effects on SH oxidation and SOH formation were prevented by hemopexin (Hpx) and ?1-microglobulin (A1M). These data suggest that free heme has a significant impact on human skeletal muscle fibres, whereby oxidative alterations in structural and contractile proteins limit contractile function. This may explain and or contribute to the weakness and increase of skeletal muscle stiffness in chronic heart failure, rhabdomyolysis, and other hemolytic diseases. Therefore, therapeutic use of Hpx and A1M supplementation might be effective in preventing heme-induced skeletal muscle alterations.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk skeletal muscle fibre contractile dysfunction heme sulfhydryl groups sulfenic acid formation chronic heart failure oxidation; hemopexin [alfa]1-microglobulin skeletal muscle myopathy
Megjelenés:	International Journal Of Molecular Sciences. - 21 : 21 (2020), p. 1-17. -
További szerzők:	Tóth Attila (1971-) (biológus) Csősz Éva (1977-) (biokémikus, molekuláris biológus) Kalló Gergő (1989-) (molekuláris biológus) Dankó Katalin (1952-2021) (belgyógyász, allergológus és klinikai immunológus) Csernátony Zoltán (1959-2023) (ortopéd sebész, traumatológus) Smith, Ann Gram, Magnus Akerström, Bo Édes István (1952-) (kardiológus) Balla György (1953-) (csecsemő és gyermekgyógyász, neonatológus) Papp Zoltán (1965-) (kardiológus, élettanász) Balla József (1959-) (belgyógyász, nephrológus)
Pályázati támogatás:	EFOP-3.6.2-16-2017-00006 EFOP OTKA-K-132828 OTKA K-84300 OTKA K-109083 OTKA GINOP-2.3.2-15-2016-00043 GINOP
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001-es BibID:	BIBFORM060830
Első szerző:	Alvarado, Gerardo
Cím:	Heme-induced contractile dysfunction in Human cardiomyocytes caused by oxidant damage to thick filament proteins / Gerardo Alvarado, Viktória Jeney, Attila Tóth, Éva Csősz, Gergő Kalló, An T. Huynh, Csaba Hajnal, Judit Kalász, Enikő T. Pásztor, István Édes, Magnus Gram, Bo Akerström, Ann Smith, John W. Eaton, György Balla, Zoltán Papp, József Balla
Dátum:	2015
ISSN:	0891-5849
Megjegyzések:	Intracellular free heme predisposes to oxidant-mediated tissue damage. We hypothesized that free heme causes alterations in myocardial contractility via disturbed structure and/or regulation of the contractile proteins. Isometric force production and its Ca2þ-sensitivity (pCa50) were monitored in permeabilized human ventricular cardiomyocytes. Heme exposure altered cardiomyocyte morphology and evoked robust decreases in Ca2þ-activated maximal active force (Fo) while increasing Ca2þ-independent passive force (Fpassive). Heme treatments, either alone or in combination with H2O2, did not affect pCa50. The increase in Fpassive started at 3 mM heme exposure and could be partially reversed by the antioxidant dithiothreitol. Protein sulfhydryl (SH) groups of thick myofilament content decreased and sulfenic acid formation increased after treatment with heme. Partial restoration in the SH group content was observed in a protein running at 140 kDa after treatment with dithiothreitol, but not in other proteins, such as filamin C, myosin heavy chain, cardiac myosin binding protein C, and α-actinin. Importantly, binding of heme to hemopexin or alpha-1-microglobulin prevented its effects on cardiomyocyte contractility, suggesting an allosteric effect. In line with this, free heme directly bound to myosin light chain 1 in human cardiomyocytes. Our observations suggest that free heme modifies cardiac contractile proteins via posttranslational protein modifications and via binding to myosin light chain 1, leading to severe contractile dysfunction. This may contribute to systolic and diastolic cardiac dysfunctions in hemolytic diseases, heart failure, and myocardial ischemia-reperfusion injury.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban Cardiomyocyte Contractile function Heme Calcium sensitivity Myosin light chain 1 Cardiac myosin binding protein C Myosin heavy chain Titin H2O2 Sulfenic acid Oxidation
Megjelenés:	Free Radical Biology And Medicine. - 89 (2015), p. 248-262. -
További szerzők:	Jeney Viktória (1971-) (vegyész, kémia tanár) Tóth Attila (1971-) (biológus) Csősz Éva (1977-) (biokémikus, molekuláris biológus) Kalló Gergő (1989-) (molekuláris biológus) Huynh, An T. Hajnal Csaba Kalász Judit (1986-) (molekuláris biológus) Pásztorné Tóth Enikő (1966-) (laboratóriumi analitikus) Édes István (1952-) (kardiológus) Gram, Magnus Akerström, Bo Smith, Ann Eaton, John W. Balla György (1953-) (csecsemő és gyermekgyógyász, neonatológus) Papp Zoltán (1965-) (kardiológus, élettanász) Balla József (1959-) (belgyógyász, nephrológus)
Pályázati támogatás:	TÁMOP-4.2.2.A-11/1/KONV-2012-0045 TÁMOP Kardiológia Kutatócsoport TÁMOP-4.2.2/B-10/1-2010-0024 TÁMOP Laki Kálmán Doktori Iskola 84300 OTKA 109083 OTKA 112333 OTKA MTA-DE MTA Vascularis Biológia, Thrombosis-Haemostasis Kutatócsoport
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001-es BibID:	BIBFORM076055
035-os BibID:	(cikkazonosító)1595 (WoS)000450704300001 (Scopus)85057036892
Első szerző:	Gáll Tamás (molekuláris biológus, mikrobiológus)
Cím:	Heme Induces Endoplasmic Reticulum Stress (HIER Stress) in Human Aortic Smooth Muscle Cells / Gáll Tamás, Pethő Dávid, Nagy Annamária, Hendrik Zoltán, Méhes Gábor, Potor László, Gram Magnus, Ảkerström, Bo, Smith Ann, Nagy Péter, Balla György, Balla József
Dátum:	2018
ISSN:	1664-042X
Megjegyzések:	Accumulation of damaged or misfolded proteins resulted from oxidative protein modification induces endoplasmic reticulum (ER) stress by activating the pathways of unfolded protein response. In pathologic hemolytic conditions, extracellular free hemoglobin is submitted to rapid oxidation causing heme release. Resident cells of atherosclerotic lesions, after intraplaque hemorrhage, are exposed to heme leading to oxidative injury. Therefore, we raised the question whether heme can also provoke ER stress. Smooth muscle cells are one of the key players of atherogenesis; thus, human aortic smooth muscle cells (HAoSMCs) were selected as a model cell to reveal the possible link between heme and ER stress. Using immunoblotting, quantitative polymerase chain reaction and immunocytochemistry, we quantitated the markers of ER stress. These were: phosphorylated elF2 alpha, Activating transcription factor-4 (ATF4), DNA-damage-inducible transcript 3 (also known as C/EBP homology protein, termed CHOP), X-box binding protein-1 (XBP1), Activating transcription factor-6 (ATF6), GRP78 (glucose-regulated protein, 78kDa) and heme responsive genes heme oxygenase-1 and ferritin. In addition, immunohistochemistry was performed on human carotid artery specimens from patients who had undergone carotid endarterectomy. We demonstrate that heme increases the phosphorylation of eiF2 alpha in HAoSMCs and the expression of ATF4. Heme also enhances the splicing of XBP1 and the proteolytic cleavage of ATF6. Consequently, there is up-regulation of target genes increasing both mRNA and protein levels of CHOP and GRP78. However, TGF beta and collagen type I decreased. When the heme binding proteins, alpha-1-microglobulin (A1M) and hemopexin (Hpx) are present in cell media, the ER stress provoked by heme is inhibited. ER stress pathways are also retarded by the antioxidant N-acetyl cysteine (NAC) indicating that reactive oxygen species are involved in heme-induced ER stress. Consistent with these findings, elevated expression of the ER stress marker GRP78 and CHOP were observed in smooth muscle cells of complicated lesions with hemorrhage compared to either atheromas or healthy arteries. In conclusion, heme triggers ER stress in a time- and dose-dependent manner in HAoSMCs. A1M and Hpx as well as NAC effectively hamper heme-induced ER stress, supporting their use as a potential therapeutic approach to reverse such a deleterious effects of heme toxicity.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk hem
Megjelenés:	Frontiers in Physiology. - 9 (2018), p. 1-25. -
További szerzők:	Pethő Dávid Nagy Annamária Hendrik Zoltán (1986-) (orvos) Méhes Gábor (1966-) (patológus) Potor László Gram, Magnus Akerström, Bo Smith, Ann Nagy Péter 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 MTA-DE MTA Vascularis Biológia, Thrombosis-Haemostasis Kutatócsoport EFOP-3.6.3-VEKOP-16-2017-00009 EFOP OTKA-112333 OTKA
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001-es BibID:	BIBFORM012889
Első szerző:	Nagy Emőke (neonatológus, gyermekgyógyász)
Cím:	Red cells, hemoglobin, heme, iron, and atherogenesis / Emőke Nagy, John W. Eaton, Viktória Jeney, Miguel P. Soares, Zsuzsa Varga, Zoltán Galajda, József Szentmiklósi, Gábor Méhes, Tamás Csonka, Ann Smith, Gregory M. Vercellotti, György Balla, József Balla
Dátum:	2010
Megjegyzések:	We investigated whether red cell infiltration of atheromatous lesions promotes the later stages of atherosclerosis. METHODS AND RESULTS: We find that oxidation of ferro (FeII) hemoglobin in ruptured advanced lesions occurs generating ferri (FeIII) hemoglobin and via more extensive oxidation ferrylhemoglobin (FeIII/FeIV=O). The protein oxidation marker dityrosine accumulates in complicated lesions, accompanied by the formation of cross-linked hemoglobin, a hallmark of ferrylhemoglobin. Exposure of normal red cells to lipids derived from atheromatous lesions causes hemolysis and oxidation of liberated hemoglobin. In the interactions between hemoglobin and atheroma lipids, hemoglobin and heme promote further lipid oxidation and subsequently endothelial reactions such as upregulation of heme oxygenase-1 and cytotoxicity to endothelium. Oxidative scission of heme leads to release of iron and a feed-forward process of iron-driven plaque lipid oxidation. The inhibition of heme release from globin by haptoglobin and sequestration of heme by hemopexin suppress hemoglobin-mediated oxidation of lipids of atheromatous lesions and attenuate endothelial cytotoxicity. CONCLUSIONS: The interior of advanced atheromatous lesions is a prooxidant environment in which erythrocytes lyse, hemoglobin is oxidized to ferri- and ferrylhemoglobin, and released heme and iron promote further oxidation of lipids. These events amplify the endothelial cell cytotoxicity of plaque components.
Tárgyszavak:	Orvostudományok Gyógyszerészeti tudományok idegen nyelvű folyóiratközlemény külföldi lapban Red cells, hemoglobin egyetemen (Magyarországon) készült közlemény
Megjelenés:	Arteriosclerosis, Thrombosis, and Vascular Biology 30 : 7 (2010), p. 1347-1353. -
További szerzők:	Eaton, John W. Jeney Viktória (1971-) (vegyész, kémia tanár) Soares, Miguel P. Varga Zsuzsa (1951-) (biokémikus, nephrológus) Galajda Zoltán (1962-) (szívsebész, érsebész) Szentmiklósi József András (1948-) (farmakológus, klinikai laboratóriumi szakorvos) Méhes Gábor (1966-) (patológus) Csonka Tamás (1984-) (pathológus) Smith, Ann Vercellotti, Gregory M. Balla György (1953-) (csecsemő és gyermekgyógyász, neonatológus) Balla József (1959-) (belgyógyász, nephrológus)
Pályázati támogatás:	OTKA-K75883 OTKA
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