Systemic and Hepatosplanchnic Hemodynamic and Metabolic Effects of the PARP Inhibitor PJ34 During Hyperdynamic Porcine Endotoxemia

Iványi, Zsolt; Hauser, Balázs; Pittner, Antje; Asfar, Pierre; Vassilev, Damian; Nalos, Marek; Altherr, Jürgen; Brückner, U. B.; Szabó, Csaba; Radermacher, Peter; Fröba, Gebhard

doi:10.1097/01.shk.0000048904.46342.22

Cited by 25 publications

(7 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, the effects of PJ34 were associated with a suppression of myocardial poly(ADP-ribose) immunoreactivity, supporting the notion of a PARP-1-dependent cardiodepressive mechanism in this clinically relevant model of septic shock [77]. Furthermore, in another model of volume-resuscitated porcine endotoxemia, PJ34 also improved cardiac output and increased stroke volume, which was most likely attributable to a direct positive inotropic effect [86].…”

Section: Parp-1 Activation Is Associated With Myocardial Depressionmentioning

confidence: 84%

Role of Nitrosative Stress and Activation of Poly(ADP-ribose) Polymerase-1 in Cardiovascular Failure Associated with Septic and Hemorrhagic Shock

Evgenov

Liaudet²

2005

CVP

View full text Add to dashboard Cite

Reactive oxygen and nitrogen species, particularly peroxynitrite, are potent inducers of tissue damage during systemic inflammatory response and circulatory shock. Recent evidence indicates that the toxicity of these species largely depends on their ability to trigger activation of the nuclear enzyme poly(adenosine 5'-diphosphate ribose) polymerase-1 (PARP-1). Following excessive activation, PARP-1 depletes the intracellular stores of its substrate, nicotinamide adenine dinucleotide, thus slowing glycolysis, generation of high energy phosphates, and mitochondrial electron transport. Consequently, the severe metabolic crisis induced by PARP-1 activation results in acute cell dysfunction and necrotic cell death. In addition, activation of PARP-1 plays an important role in the upregulation of inflammatory cascades via a functional association with mitogen-activated protein kinases and several transcription factors, such as nuclear factor kappa B, resulting in augmented expression of pro-inflammatory cytokines, chemokines, adhesion molecules, and enzymes. In severe sepsis and hemorrhage, PARP-1 activation has emerged as one of the central mechanisms of systemic inflammation, endothelial dysfunction, peripheral vascular failure, and reduction of cardiac contractility. Innovative therapeutic strategies based on the pharmacological inhibition of PARP-1 catalytic activity might provide benefits by preventing tissue injury, organ dysfunction, and lethality associated with these conditions.

show abstract

Section: Parp-1 Activation Is Associated With Myocardial Depressionmentioning

confidence: 84%

Role of Nitrosative Stress and Activation of Poly(ADP-ribose) Polymerase-1 in Cardiovascular Failure Associated with Septic and Hemorrhagic Shock

Evgenov

Liaudet²

2005

CVP

View full text Add to dashboard Cite

show abstract

“…The most significant amelioration was seen on MAP, RBF and renal oxygen metabolism. It is reported that suppression of PARP could influence both vascular and hemodynamic function [15,25] by upregulating the CO, attenuating cardiomyocyte dysfunction and reducing the SVR [26,27,28]. Hans et al [29] presented that PARP-1 gene deletions prominently prevent the faltering of hemodynamic parameters in cardiac hypertrophy by directly effecting MMP-9 and TIMP-2 expression.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Poly-(ADP-Ribose) Polymerase Protects the Kidney in a Canine Model of Endotoxic Shock

Liu

et al. 2015

Nephron

View full text Add to dashboard Cite

Poly-(ADP-ribose) polymerases (PARPs), a super family of enzymes, play important roles in preserving genomic integrity, regulating transcriptions, protecting telomeres and determining cell fate. PARP overactivation leads to metabolic disorder and cell injury via depletion of energy substance. However, it is still unclear whether PARP overactivation happens during acute kidney injury (AKI) caused by endotoxic shock (ES). Here, we built a canine model of lipopolysaccharide-induced ES to explore the role of PARP during the development AKI. We also used an intravenous injection of 3-aminobenzamide (3-AB) to further explore whether PARP inhibition rescues the kidney from injury. Cell fate and energy metabolism were detected to explore the underlying mechanisms. As a result, Western blot and immunohistochemistry assays showed PARP overactivation in the very early phase of ES. Through PARP inhibition by 3-AB, we observed significant improvement of systemic hemodynamics, renal hemodynamics, renal oxygen metabolism and renal tubular cell apoptosis. These findings indicated that overactivation of PARP plays an important role in septic AKI. Inhibition of PARP overactivation may protect renal function against hemodynamic disorder, renal metabolism disturbance and renal cell apoptosis during endotoxic AKI.

show abstract

“…However, 3-aminobenzamide is considered to be a poor inhibitor of PARP and has pronounced toxicity in vivo. On the other hand, novel, potent PARP-1 inhibitors were found to protect against LPS-induced tissue damage Ivanyi et al, 2003;Veres et al, 2003). Disruption of the PARP gene suppresses LPS-induced cytokine expression and NF-B activation (Oliver et al, 1999).…”

mentioning

confidence: 99%

Regulation of Kinase Cascades and Transcription Factors by a Poly(ADP-Ribose) Polymerase-1 Inhibitor, 4-Hydroxyquinazoline, in Lipopolysaccharide-Induced Inflammation in Mice

Veres¹,

Radnai²,

Gallyas³

et al. 2004

J Pharmacol Exp Ther

117

View full text Add to dashboard Cite

Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) is involved in numerous pathophysiological conditions. Because PARP-1 knockout mice are resistant to endotoxininduced shock and inhibitors of the enzyme were reported to have similar beneficial properties, we investigated the effect of 4-hydroxyquinazoline (4-HQN), a potent PARP-1 inhibitor, on the modulation of kinase cascades and the regulation of transcription factors in a rodent septic shock model. T2-weighted magnetic resonance imaging showed the pattern of anatomical localization of the inflammatory response in bacterial lipopolysaccharide (LPS)-treated mice and the anti-inflammatory effect of the PARP-1 inhibitor. We have found that 4-HQN activated the phosphatidylinositol 3 (PI3)-kinase/Akt pathway in lung, liver, and spleen, and down-regulated two elements of the MAP kinase system. Namely, it dramatically attenuated the activation of the LPS-induced extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein (MAP) kinase in a tissue-specific manner. Furthermore, phosphorylation of p90RSK, a downstream target of ERK1/2, showed a similar pattern of down-regulation as did the phosphorylation of ERK1/2 and p38 after LPS and 4-HQN treatment. As a consequence of the aforementioned effects on the kinase pathways, 4-HQN decreased the activation of transcription factor nuclear factor-B (NF-B) and activator protein 1 (AP-1) in LPS-induced endotoxic shock. Our results provide evidence for the first time that the beneficial effects of PARP inhibition in endotoxic shock, such as attenuation of NF-B-and AP-1 transcription factor activation, are mediated, at least partially, through the regulation of the PI3-kinase/Akt pathway and MAP kinase cascades.

show abstract

Systemic and Hepatosplanchnic Hemodynamic and Metabolic Effects of the PARP Inhibitor PJ34 During Hyperdynamic Porcine Endotoxemia

Cited by 25 publications

References 34 publications

Role of Nitrosative Stress and Activation of Poly(ADP-ribose) Polymerase-1 in Cardiovascular Failure Associated with Septic and Hemorrhagic Shock

Role of Nitrosative Stress and Activation of Poly(ADP-ribose) Polymerase-1 in Cardiovascular Failure Associated with Septic and Hemorrhagic Shock

Inhibition of Poly-(ADP-Ribose) Polymerase Protects the Kidney in a Canine Model of Endotoxic Shock

Regulation of Kinase Cascades and Transcription Factors by a Poly(ADP-Ribose) Polymerase-1 Inhibitor, 4-Hydroxyquinazoline, in Lipopolysaccharide-Induced Inflammation in Mice

Contact Info

Product

Resources

About