Abstract 4469: Carbamoylating activity associated with the antitumor prodrug Laromustine inhibits angiogenesis in vitro by inducing ASK1-dependent endothelial cell death

Author(s):  
Roxanne Ghazvinian ◽  
V. Alexandra Praggastis ◽  
Xianghong Li ◽  
Wei Zhang ◽  
Edmund J. Klinkerch ◽  
...  
Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3972-3972
Author(s):  
George T. Roberts ◽  
Muhammad A. Chishti ◽  
Fallah H. Al-Mohanna ◽  
Raafat M. El-Sayed ◽  
Abderezak Bouchama

Abstract Introduction: Ultrastructural evidence of endothelial cell (EC) injury has been associated with diffuse microvascular thrombosis in human heatstroke (HS). In vitro studies have also shown that heat stress accelerates apoptotic cell death. Using a recently described baboon model of heatstroke, we sought to examine pathological changes in the vascular endothelium and whether apoptosis is a mechanism of endothelial cell death. Hypothesis: Major structural vascular endothelium alterations occur in HS and apoptosis is a mechanism of endothelial cell death in HS. Methods: Anesthetized baboons (Papio hamadyras) were heat-stressed in a neonatal incubator maintained at 44 1.5 °C, until rectal temperature attained 42.5°C (moderate heatstroke; n =4) or systolic blood pressure fell to < 90 mm Hg (severe heatstroke n =4). Animals were resuscitated with normal saline and allowed to cool at room temperature. Four sham-heated animals served as control group. Spleen, liver, heart, kidney, gut, lung and adrenal tissue were obtained either by immediate autopsy in non-survivors or after euthanasia at 72-h for survivors. Vascular endothelium ultrastructure was evaluated by transmission electron microscopy (TEM) of ultra-thin tissue sections. Biological activity of EC was determined by light microscopy (LM) using a polyclonal antibody targeting von Willebrand Factor (vWF). Apoptosis was assessed, also in tissue sections, by deoxyuridine triphosphate nick end-labeling (TUNEL) procedure. Results: In heatstroke animals, there were marked EC changes in lungs, spleen, jejunum, kidneys and liver, demonstrated by TEM, as increased cytoplasmic membrane convolutions that included formation of villi projecting into the vessel lumina, and increase in the width of the gaps between ECs. Migration of neutrophils, platelets and erythrocytes through these widened gaps was noted. Weibel-Palade bodies were increased both in size and number in EC of jejunum, lungs and kidneys. This increase correlated with increased endothelial expression of immunologically detectable vWF. TEM also showed that there was increased apoptosis manifested by nuclear chromatin condensation and karyorrhexis and formation of cytoplasmic myelin whorls. Increased EC apoptosis was also observed by TUNEL in the jejunum, lungs, liver and spleen. All these changes were greater in animals with severe HS than in animals with moderate HS, whereas sham heated control animals showed no significant changes. Conclusion: Widespread EC injury with apoptotic cell death is consistent with the hypothesis that the endothelium may play a pathogenic role in heatstroke.


2007 ◽  
Vol 292 (3) ◽  
pp. R1174-R1183 ◽  
Author(s):  
Sonia Brault ◽  
Fernand Gobeil ◽  
Audrey Fortier ◽  
Jean-Claude Honoré ◽  
Jean-Sébastien Joyal ◽  
...  

Oxidant stress plays a significant role in hypoxic-ischemic injury to the susceptible microvascular endothelial cells. During oxidant stress, lysophosphatidic acid (LPA) concentrations increase. We explored whether LPA caused cytotoxicity to neuromicrovascular cells and the potential mechanisms thereof. LPA caused a dose-dependent death of porcine cerebral microvascular as well as human umbilical vein endothelial cells; cell death appeared oncotic rather than apoptotic. LPA-induced cell death was mediated via LPA1 receptor, because the specific LPA1 receptor antagonist THG1603 fully abrogated LPA's effects. LPA decreased intracellular GSH levels and induced a p38 MAPK/JNK-dependent inducible nitric oxide synthase (NOS) expression. Pretreatment with the antioxidant GSH precursor N-acetyl-cysteine (NAC), as well as with inhibitors of NOS [ Nω-nitro-l-arginine (l-NNA); 1400W], significantly prevented LPA-induced endothelial cell death (in vitro) to comparable extents; as expected, p38 MAPK (SB203580) and JNK (SP-600125) inhibitors also diminished cell death. LPA did not increase indexes of oxidation (isoprostanes, hydroperoxides, and protein nitration) but did augment protein nitrosylation. Endothelial cytotoxicity by LPA in vitro was reproduced ex vivo in brain and in vivo in retina; THG1603, NAC, l-NNA, and combined SB-203580 and SP600125 prevented the microvascular rarefaction. Data implicate novel properties for LPA as a modulator of the cell redox environment, which partakes in endothelial cell death and ensued neuromicrovascular rarefaction.


2008 ◽  
Vol 199 (2) ◽  
pp. 465-466
Author(s):  
Lingfang Zeng ◽  
Anna Zampetaki ◽  
Andriana Margariti ◽  
Hongling Li ◽  
Zhongyi Zhang ◽  
...  

2021 ◽  
Vol 12 ◽  
Author(s):  
Te-Sheng Lien ◽  
Der-Shan Sun ◽  
Cheng-Yeu Wu ◽  
Hsin-Hou Chang

Typically occurring during secondary dengue virus (DENV) infections, dengue hemorrhagic fever (DHF) causes abnormal immune responses, as well as endothelial vascular dysfunction, for which the responsible viral factor remains unclear. During peak viremia, the plasma levels of virion-associated envelope protein domain III (EIII) increases to a point at which cell death is sufficiently induced in megakaryocytes in vitro. Thus, EIII may constitute a virulence factor for endothelial damage. In this study, we examined endothelial cell death induced by treatment with DENV and EIII in vitro. Notably, pyroptosis, the major type of endothelial cell death observed, was attenuated through treatment with Nlrp3 inflammasome inhibitors. EIII injection effectively induced endothelial abnormalities, and sequential injection of EIII and DENV-NS1 autoantibodies induced further vascular damage, liver dysfunction, thrombocytopenia, and hemorrhage, which are typical manifestations in DHF. Under the same treatments, pathophysiological changes in the Nlrp3 inflammasome–deficient mice were notably reduced compared with those in the wild-type mice. These results suggest that the Nlrp3 inflammasome constitutes a potential therapeutic target for treating DENV-induced hemorrhage in DHF.


2015 ◽  
Vol 47 (7) ◽  
pp. 1362-1371 ◽  
Author(s):  
QIONG WANG ◽  
FRANÇOIS GUERRERO ◽  
ALEKSANDRA MAZUR ◽  
KATE LAMBRECHTS ◽  
PETER BUZZACOTT ◽  
...  

2001 ◽  
Vol 90 (6) ◽  
pp. 2279-2288 ◽  
Author(s):  
Martin H. Beauchamp ◽  
Ana Katherine Martinez-Bermudez ◽  
Fernand Gobeil ◽  
Anne Marilise Marrache ◽  
Xin Hou ◽  
...  

Microvascular degeneration is an important event in oxygen-induced retinopathy (OIR), a model of retinopathy of prematurity. Because oxidant stress abundantly generates thromboxane A2(TxA2), we tested whether TxA2plays a role in retinal vasoobliteration of OIR and contributes to such vascular degeneration by direct endothelial cytotoxicity. Hyperoxia-induced retinal vasoobliteration in rat pups (80% O2exposure from postnatal days 5–14) was associated with increased TxB2generation and was significantly prevented by TxA2synthase inhibitor CGS-12970 (10 mg · kg−1· day−1) or TxA2-receptor antagonist CGS-22652 (10 mg · kg−1· day−1). TxA2mimetics U-46619 (EC5050 nM) and I-BOP (EC505 nM) caused a time- and concentration-dependent cell death of neuroretinovascular endothelial cells from rats as well as newborn pigs but not of smooth muscle and astroglial cells; other prostanoids did not cause cell death. The peroxidation product 8-iso-PGF2, which is generated in OIR, stimulated TxA2formation by endothelial cells and triggered cell death; these effects were markedly diminished by CGS-12970. TxA2-dependent neuroretinovascular endothelial cell death was mostly by necrosis and to a lesser extent by apoptosis. The data identify an important role for TxA2in vasoobliteration of OIR and unveil a so far unknown function for TxA2in directly triggering neuroretinal microvascular endothelial cell death. These effects of TxA2might participate in other ischemic neurovascular injuries.


Author(s):  
Jiunn-Tay Lee ◽  
Giia-Sheun Peng ◽  
Shao-Yuan Chen ◽  
Chang-Hung Hsu ◽  
Chun-Chieh Lin ◽  
...  

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