The role of poly(ADP-ribose) polymerase (PARP) in the autonomous proliferative response of endothelial cells to hypoxia☆

Abdallah, Yaser; Gligorievski, Dragan; Kasseckert, Sascha; Dieterich, Lukas; Schäfer, Matthias; Kuhlmann, Christoph; Noll, Thomas; Sauer, Heinrich; Piper, H. M.; Schäfer, Claudia

doi:10.1016/j.cardiores.2006.11.027

Cited by 21 publications

(25 citation statements)

References 14 publications

(28 reference statements)

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“…This is distinctly different from our previous studies where cell cycle arrest was achieved by moderate serum restriction (1,33,34). Here, a maneuver was used to go beyond a cell cycle arrest and expose endothelial cells to a severe challenge that emulates in part pro-apoptotic conditions in the ischemic tissue.…”

Section: Discussionmentioning

confidence: 70%

“…Phosphorylation of ERK 2, indicating its activation, occurred as a rapid but transient response to hypoxia. Accordingly, we and others (1,21,33,36,42) have previously demonstrated that MEK/ERK are transiently activated during onset of hypoxia. In this study we found, that pro-apoptotic Bad at its inhibitory phosphorylation site Ser112 (12,35) was also transiently increased during hypoxia.…”

Section: Discussionmentioning

confidence: 89%

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Transient hypoxia induces ERK-dependent anti-apoptotic cell survival in endothelial cells

Härtel

Holl

Arshad

et al. 2010

American Journal of Physiology-Cell Physiology

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Ischemia-induced apoptosis of endothelial cells may contribute to tissue injury, organ failure, and transplantation rejection. However, little is known about survival mechanisms capable to counteract endothelial apoptosis. This study investigated the potential role of an endogenous anti-apoptotic response elicited by transient hypoxia, capable to avert ongoing apoptosis in endothelial cells. Experiments were carried out in three different types of cultured endothelial cells (human umbilical vein, pig aorta, and from rat coronary microvasculature). As a pro-apoptotic challenge endothelial cells were cultured in serum-free medium and subjected to hypoxia for 2 h. We found that transient hypoxia reduced caspase 3 activation within 1 h of hypoxia. Accordingly, the number of apoptotic cells was reduced after 24 h of reoxygenation. This was true for all three cell types analyzed. Analysis of Akt and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways revealed that hypoxia induced a transient activation of ERK 2 but not of Akt. ERK 2 phosphorylation preceded the phosphorylation of pro-apoptotic molecule Bad at Ser112, an inhibitory phosphorylation site specific for ERK. The protective effects of hypoxia regarding Bad phosphorylation, caspase 3 activation, and apoptosis were abolished by MEK 1/2 inhibitors, PD98059 or UO126, as well as by antisense oligonucleotides directed against ERK 1/2. Furthermore, inhibition of this pathway inhibited hypoxia-induced increase in mitochondrial membrane potential. The present study demonstrates that transient hypoxia induces a novel survival mechanism that protects endothelial cells against apoptosis. This endogenous process involves MEK/ERK-mediated inhibition of the pro-apoptotic molecule Bad and caspase 3.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 89%

Transient hypoxia induces ERK-dependent anti-apoptotic cell survival in endothelial cells

Härtel

Holl

Arshad

et al. 2010

American Journal of Physiology-Cell Physiology

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“…PARP1 is a downstream effector of NADPH oxidase and ROS [26]. We showed that TGF-β1 treatment increased PARP activity; and knockdown of PARP1 prevented TGF-β1-induced increase in PARP activity.…”

Section: Discussionmentioning

confidence: 77%

Poly(ADP-ribose) Polymerase 1 Is Indispensable for Transforming Growth Factor-β Induced Smad3 Activation in Vascular Smooth Muscle Cell

Huang

Wang

et al. 2011

PLoS ONE

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BackgroundTransforming growth factor type-β (TGF-β)/Smad pathway plays an essential role in vascular fibrosis. Reactive oxygen species (ROS) generation also mediates TGF-β signaling-induced vascular fibrosis, suggesting that some sort of interaction exists between Smad and redox pathways. However, the underlying molecular mechanism is largely unknown. This study aims to investigate the influence of poly(ADP-ribose) polymerase 1 (PARP1), a downstream effector of ROS, on TGF-β signaling transduction through Smad3 pathway in rat vascular smooth muscle cells (VSMCs).Methods and ResultsTGF-β1 treatment promoted PARP1 activation through induction of ROS generation in rat VSMCs. TGF-β1-induced phosphorylation and nuclear accumulation of Smad3 was prevented by treatment of cells with PARP inhibitor, 3-aminobenzamide (3AB) or N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-2-(N,N-dimethylamino)acetami (PJ34), or PARP1 siRNA. TGF-β1 treatment promoted poly(ADP-ribosy)lation of Smad3 via activation of PARP1 in the nucleus. Poly(ADP-ribosy)lation enhanced Smad-Smad binding element (SBE) complex formation in nuclear extracts and increased DNA binding activity of Smad3. Pretreatment with 3AB, PJ34, or PARP1 siRNA prevented TGF-β1-induced Smad3 transactivation and expression of Smad3 target genes, including collagen Iα1, collagen IIIα1 and tissue inhibitor of metalloproteinase 1, in rat VSMCs.ConclusionsPARP1 is indispensable for TGF-β1 induced Smad3 activation in rat VSMCs. Targeting PARP1 may be a promising therapeutic approach against vascular diseases induced by dysregulation of TGF-β/Smad3 pathway.

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“…Recently, Lcarnitine has been proposed as a potential adjuvant treatment to improve anaemia, thrombocytopenia, leukopenia and immunological function. [68][69][70][71][72][73] In a recent study, L-carnitine added to Peg-IFN-α plus ribavirin led to less decrease of platelet count during antiviral therapy. 74 Some studies indicate that L-carnitine modulates platelet functions and production through antioxidant mechanisms and the inhibition of the arachidonic acid cascade.…”

Section: L-carnitinementioning

confidence: 98%

Chronic hepatitis C-associated thrombocytopenia: aetiology and management

Fouad

2013

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Thrombocytopenia is perhaps the most common haematological abnormality in patients with chronic hepatitis C virus (HCV) infection. In these patients, the presence of thrombocytopenia may be a limiting factor when considering antiviral therapy and may be associated with decreased sustained virological response rates. Thrombocytopenia may interfere with diagnostic procedures such as liver biopsy, because of risk of bleeding.Pathogenetic mechanisms include hypersplenism secondary to portal hypertension, bone marrow suppression resulting from either HCV itself or interferon treatment, and aberrations of the immune system resulting in the formation of anti-platelet antibodies and/or immunecomplexes that bind to platelets and facilitate their premature clearance. The ability to increase platelet levels could significantly reduce the need for platelet transfusions and facilitate the use of interferon-based antiviral therapy and other medically indicated treatments in patients with liver disease. Therapeutic options include pharmacological and non-pharmacological therapies. This review summarizes the available data on these therapeutic options. KEYWORDS: thrombocytopenia, hepatitis C virus (HCV), cytokines Definition and prevalenceThrombocytopenia has been defined as a platelet count <150,000 cells/µL. In a recent systematic review, the definitions of thrombocytopenia varied between studies and were based either on platelet counts, with threshold levels ranging between <100,000 cells/µL and <180,000 cells/µL or on criteria set in haematological guidelines. The prevalence of thrombocytopenia related to chronic liver disease has been reported as 15% to 70% in patients with advanced fibrosis and portal hypertension, depending on the stage of the disease and the platelet level used to define thrombocytopenia. In patients with chronic HCV infection, the prevalence of thrombocytopenia ranged from 0.16% to 45.4% and more than half of the studies reported a prevalence of 24% or more. 1 Aetiology of thrombocytopenia in patients with chronic HCVThe pathophysiology of thrombocytopenia in patients with HCV-related chronic liver disease is complex and involves the interaction of multiple factors. In general, these factors may be

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The role of poly(ADP-ribose) polymerase (PARP) in the autonomous proliferative response of endothelial cells to hypoxia☆

Abstract: PARP represents a downstream effector of NADP(H) oxidase and acts as a necessary intermediate step for the hypoxic proliferative response of endothelial cells.

Cited by 21 publications

References 14 publications

Transient hypoxia induces ERK-dependent anti-apoptotic cell survival in endothelial cells

Transient hypoxia induces ERK-dependent anti-apoptotic cell survival in endothelial cells

Poly(ADP-ribose) Polymerase 1 Is Indispensable for Transforming Growth Factor-β Induced Smad3 Activation in Vascular Smooth Muscle Cell

Chronic hepatitis C-associated thrombocytopenia: aetiology and management

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