PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3β pathway☆

Pálfi, Anita; Tóth, Ambrus; Hanto, Katalin; Deres, Péter; Szabados, Eszter; Szereday, Z; Kulcsár, Gyula; Kálai, Tamás; Hideg, Kálmán; Gallyas, Ferenc; Sümegi, Balázs; Tóth, Kálmán; Halmosi, Róbert

doi:10.1016/j.yjmcc.2006.03.427

Cited by 51 publications

(54 citation statements)

References 46 publications

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“…It is likely that the increased expression of these molecules in tobacco-exposed rats not only signifies their role in altered remodeling in the myocardium, but also the direct effect of tobacco exposure on the expression of these tissue repair participants. Similarly, tobacco exposure also resulted in a significantly higher mRNA expression of PARP, a marker of DNA damage and indicator of apoptosis, 43,44 suggesting that the more extensive MI in tobacco-exposed rats is also accompanied by an increase in cardiomyocyte apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

Khanna

Mehra

2012

Laboratory Investigation

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The contribution of chronic tobacco exposure in determining post-myocardial infarction (MI) left ventricular (LV) remodeling and possible therapeutic strategies has not been investigated systematically. In this small animal investigation, we demonstrate that chronic tobacco smoke exposure leading up to acute MI in rats is associated with greater histological extent of myocardial necrosis and consequent worse LV function. These findings are associated with increased transcriptomic expression of pro-inflammatory cytokines, tissue repair molecules and markers of oxidative stress in the myocardium. The results demonstrate that an N-acetyl cysteine (NAC) treatment significantly reduced tobacco-exposed induced infarct size and percent fractional shortening. A significantly increased LV end-systolic diameter was observed in tobacco-exposed sham compared to tobacco-naïve sham (4.92 ± 0.41 vs 3.45 ± 0.33; Po0.05), and tobacco-exposed MI compared to tobacco-naïve MI (8.24±0.3 vs 6.1±0.49; Po0.01) rats. Decreased intracardiac mRNA expression of the markers of inflammation, tissue repair and oxidative stress and circulating levels of pro-inflammatory cytokines accompanied these positive effects of NAC. The treatment of tobacco-exposed MI rats with NAC resulted in significantly increased levels of intracardiac mRNA expression of antioxidants, including superoxide dismutase, thioredoxin and nuclear factor-E2-related factor 2, as well as circulating levels of glutathione (7 ± 0.12 vs 10 ± 0.18; Pp0.001), where the levels were almost identical to the tobacco-naïve sham rats. These findings identify a novel post-infarction therapy for amelioration of the adverse effects of tobacco exposure on the infracted myocardium and advocate the use of dietary supplement antioxidants for habitual smokers to prevent and reverse cardiovascular adverse effects in the absence of successful achievement of cessation of smoking. Globally, tobacco smoke exposure remains a significant risk for the development of acute myocardial infarction (MI) irrespective of ethic or gender disparities. Exposure to tobacco smoke increases inflammation, oxidative stress 1-10 and decreases antioxidant expression. [11][12][13][14][15] Direct and indirect studies have demonstrated that oxidative stress from reactive oxygen species (ROS) generated through mitochondria, xanthine oxidase, and the NADPH oxidase system 16-21 is one of the important factors in the pathogenesis of myocardial ischemia. Decreased infarct size in superoxide dismutase (SOD)-producing transgenic mice suggests direct evidence for the role of involvement of ROS in MI. 22,23 In limited investigations, the use of antioxidants such as mercaptopropionyl glycine, edaravone and probucol have demonstrated varied effects on remodeling in animal models of MI, [24][25][26][27][28][29][30][31][32] with improvement in collagen content and histological changes. In this study, we sought to delineate the role of chronic tobacco smoke leading up to an acute MI by focusing on oxidative stress coupled with inflammat...

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Section: Discussionmentioning

confidence: 99%

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

Khanna

Mehra

2012

Laboratory Investigation

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“…everal studies have shown that inhibiting poly-ADP ribose polymerase-1 (PARP-1) attenuates organ dysfunction in settings such as postmyocardial infarction remodeling, 1 ischemia-reperfusion injury, 2 diabetic retinopathy, 3 septic shock, 4 diabetes, 3,5 and atherosclerosis. 6 A major feature of atherosclerosis includes increased levels of reactive nitrosative species (RNS) and reactive oxygen species (ROS) associated with damage to cell membranes and DNA.…”

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confidence: 99%

PARP-1 Inhibition Prevents Oxidative and Nitrosative Stress–Induced Endothelial Cell Death via Transactivation of the VEGF Receptor 2

Mathews

Berk

2008

ATVB

106

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Objective-PARP-1, a DNA base repair enzyme, is activated by DNA breaks induced by oxidative (ROS) and nitrosative (RNS) stress. By consuming NAD ϩ , PARP-1 activation can lead to ATP depletion and cell death. Studies suggest that inhibiting PARP-1 activity can attenuate pathologies associated with vascular smooth muscle and endothelial dysfunction. PARP-1 inhibition can also activate the prosurvival serine/threonine kinase, Akt. Vascular endothelial growth factor (VEGF) regulates endothelial cell survival via Akt activation downstream of VEGF receptor 2 (VEGFR2) activation. Here we investigated the hypothesis that PARP-1 inhibition protects human umbilical vein endothelial cells (HUVECs) from ROS-and RNS-induced cell death by limiting NAD ϩ depletion and by activating a prosurvival signaling pathway via VEGFR2 phosphorylation. Methods and Results-We activated PARP-1 in HUVECs by treatment with hydrogen peroxide (H 2 O 2 ) and peroxynitrite (ONOO Ϫ ). Both depleted HUVECs of NAD ϩ and ATP, processes that were limited by the PARP-1 inhibitor, PJ34. ONOO Ϫ and H 2 O 2 -induced cell death and apoptosis were attenuated in cells treated with PJ34 or PARP-1 siRNA. PARP-1 inhibition increased Akt, BAD, and VEGFR2 phosphorylation in HUVECs and in PJ34-treated rabbit aortas. The VEGFR2-specific tyrosine kinase inhibitor SU1498 decreased PARP-1 inhibition-mediated phosphorylation of VEGFR2 and Akt, and also reversed survival effects of PJ34. Finally, PARP-1 inhibition protected cells from death induced by serum starvation, evidence for a role in cell survival independent of energy protection. Conclusions-PARP-1 inhibition prevents ROS-and RNS-induced HUVEC death by maintaining cellular energy in the form of NAD ϩ and ATP, and also by activating a survival pathway via VEGFR2, Akt, and BAD phosphorylation. Key Words: PARP inhibition Ⅲ endothelial cell survival Ⅲ VEGF receptor 2 Ⅲ oxidative stress S everal studies have shown that inhibiting poly-ADP ribose polymerase-1 (PARP-1) attenuates organ dysfunction in settings such as postmyocardial infarction remodeling, 1 ischemia-reperfusion injury, 2 diabetic retinopathy, 3 septic shock, 4 diabetes, 3,5 and atherosclerosis. 6 A major feature of atherosclerosis includes increased levels of reactive nitrosative species (RNS) and reactive oxygen species (ROS) associated with damage to cell membranes and DNA. 7,8 It is not surprising therefore that PARP-1 inhibition was also shown to limit endothelial dysfunction and atherosclerosis in the ApoE Ϫ/Ϫ mouse. 6,9 High levels of ROS and RNS, such as occur in ischemia-reperfusion injury, inflammation, and diabetes mellitus, induce DNA single-strand breaks and activate poly-ADP ribose polymerase-1 (PARP-1). 10 PARP-1 is a zinc finger protein that belongs to a family of 18 identified genes that transcribe poly(ADP-ribose) polymerases, enzymes that catalyze the covalent transfer of poly-ADP units from NAD ϩ to acceptor proteins. PARP-1 has 3 functional domains: a DNA-binding domain (containing a nuclear localization signal), an automodificatio...

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“…A fenti jelátviteli utak nukleárisan az NF-κB aktiválása révén már közvetlenül a génexpressziót befolyásolják. Az angiotenzin-II-stimulus, továbbá a kalcium-kalmodulin-kináz II (CaMKII) ROS-függő aktiválásán keresztül szintén a szívizomsej-tek károsodásához vezet [19,20]. A bal kamrai nyomás-terhelésre és GPCR-agonistákra adott celluláris válaszre-akcióban a korábban említett NOX-2 és NOX-4 szerepét is ki kell emelni, amelyek tovább fokozzák az intracelluláris és intramitokondriális O 2 -és a H 2 O 2 termelődését, ezzel felerősítik a fentebb említett ROS mediálta utakat.…”

Section: A Ros Következményei Szívelégtelenségbenunclassified

Az oxidatív stressz szerepe szívelégtelenségben

Gal

Halmosi

2015

Orvosi Hetilap

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Az oxidatív stressz fontos szerepet játszik a szívelégtelenség kialakulásában. A szívizomzatban megtalálható összes sejttípus részt vesz az oxigén-és a nitrogén-szabadgyökök termelésében. A reaktívoxigén-származékok potenciális forrásának a szívben a NADPH-oxidáz, a nitrogén-oxid-szintázok, a lipoxigenázok, a ciklooxigenázok, a xantinoxidáz, a citokróm P450 enzimek, illetve a mitokondriális légzési lánc elemei tekinthetők. A reaktívoxigén-származékok okozta károsodás magában foglalja mind a vascularis rendszer (endotheldiszfunkció, atherosclerosis), mind a myocardium direkt károsodását (bal kamrai remodelling). A reaktívoxigén-származékok sejtszinten fehérje-, lipid-és DNSkárosodáshoz, valamint számos jelátviteli út modifi kációjához vezetnek, amelyek központi szerepet töltenek be a remodelling, a hypertrophia és a kamrai dilatatio kialakulásában. Orv. Hetil., 2015, 156(47), 1916-1920 Kulcsszavak: oxidatív stressz, reaktívoxigén-származékok, remodelling, szívelégtelenség The role of oxidative stress in heart failureOxidative stress plays an important role in the development of heart failure. Reactive oxygen and nitrogen species can be generated in all cell types that can be found in the myocardium. Potential sources of reactive oxygen species are the NADPH oxidases, nitric oxide synthase, lipoxygenases, cyclooxygenase, xanthine oxidase, cytochrome P450 enzymes, and the mitochondrial respiratory chain. The reactive oxygen species mediated damages are implicated in both the vascular system (endothelial dysfunction, atherosclerosis) and the myocardium (remodeling). Oixidative stress causes lipid and protein oixidation as well as single stranded DNA breaks and induces changes in signaling pathways which serve as central transducers of cardiac hypertrophic growth, remodeling and/or ventricular dilatation.Keywords: oxidative stress, reactive oxygen species, remodeling, heart failure Gál, R., Halmosi, R. [The role of oxidative stress in heart failure]. Orv. Hetil., 2015Hetil., , 156(47), 1916Hetil., -1920 Rövidítések Akt-1/GSK-3β = glikogénszintáz-kináz-3β; CaMKII = kalcium-kalmodulin-kináz II; COX = ciklooxigenáz; eNOS = endothelialis NOS; ERK 1/2 = extracellular signal-regulated protein kinase 1/2; ESR = elektronspin-rezonancia; JNK = c-Jun NH2-terminális kináz; NO = nitrogén-monoxid; NOS = nitrogén-oxid-szintáz; p38-MAPK = p38 mitogénaktivált fehérje kináz; PARP-1 = poli(ADP-ribóz) polimeráz-1; PKC = pro teinkináz C; ROS = (reactive oxygen species) reaktívoxi-gén-származékok Az oxidatív stressz a reaktívoxigén-vagy nitrogénerede-tű szabad gyökök keletkezése és az antioxidáns védő-rendszerek közötti egyensúly megbomlása, a sejtek oxidoredukciós állapotának megváltozása során lép fel, amikor a redoxállapot az oxidáció irányába tolódik el. Az oxidatív stressz következtében a sejtek szinte mindegyik biomolekulája sérülhet [1]. Nem meglepő ezért, hogy a szabad gyökös károsodások fontos patogenetikai ténye-zők a legtöbb betegség kialakulásában. Így van ez a szív-ér rendszeri betegségek és a szívelégtelenség esetén is.A ...

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PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3β pathway☆

Cited by 51 publications

References 46 publications

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

PARP-1 Inhibition Prevents Oxidative and Nitrosative Stress–Induced Endothelial Cell Death via Transactivation of the VEGF Receptor 2

Az oxidatív stressz szerepe szívelégtelenségben

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