Lipopolysaccharide initiates a TRAF6-mediated endothelial survival signal

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4520-4526 ◽  
Author(s):  
Fred Wong ◽  
Christopher Hull ◽  
Rachel Zhande ◽  
Jennifer Law ◽  
Aly Karsan
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Survival ◽  
Nuclear Factor Κb ◽  
Phosphatidylinositol 3 Kinase ◽  
Survival Signal ◽  
Survival Pathways ◽  
Survival Pathway ◽  
Mitogen Activated Protein ◽  
Endothelial Cell Death

Abstract Similar to tumor necrosis factor (TNF), bacterial lipopolysaccharide (LPS) elicits parallel apoptotic and antiapoptotic pathways in endothelial cells. The overall result is that there is minimal endothelial cell death in response to LPS without inhibition of the cytoprotective pathway. While the TNF-induced death and survival pathways have been relatively well elucidated, much remains to be learned about LPS signaling events in this regard. It is known that the transcription factor nuclear factor-κB (NF-κB) provides a critical cell survival signal in response to TNF, but is not an essential component of the LPS-induced survival pathway. The TNF receptor-associated factor 6 (TRAF6) is a major effector of multiple LPS-induced signals, including a c-Jun N-terminal kinase (JNK)-mediated apoptotic response. In this report we demonstrate that following LPS stimulation, TRAF6 also transmits an important endothelial cell survival signal in a situation of complete NF-κB blockade. In response to LPS, TRAF6 activates the phosphatidylinositol 3′-kinase (PI3K)/Akt pathway, but not ERK1/2 mitogen-activated protein kinases (MAPKs) in endothelial cells. Activation of PI3K signals a critical antiapoptotic pathway in response to LPS in endothelial cells, whereas ERK1/2 does not. Thus TRAF6 acts as a bifurcation point of the LPS-initiated death and survival signals in endothelial cells. (Blood. 2004;103:4520-4526)

Erythropoietin promotes survival of primary human endothelial cells through PI3K-dependent, NF-κB-independent upregulation of Bcl-xL

2007 ◽  
Vol 292 (5) ◽  
pp. H2467-H2474 ◽  
Author(s):  
Rachel Zhande ◽  
Aly Karsan
Keyword(s):  
Endothelial Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Erythroid Progenitors ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Survival Pathway ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Endothelial Cell Death ◽  
Underlying Mechanisms

Erythropoietin (EPO) regulates the production of red blood cells primarily by preventing apoptosis of erythroid progenitors. More recently, however, EPO has emerged as a major cytoprotective cytokine in several nonhemopoietic tissues in the setting of stress or injury. The underlying mechanisms of the protective responses of EPO have not been fully defined. Here we show that EPO triggers a phosphatidylinositol 3-kinase-(PI3K)-dependent survival pathway that counteracts endothelial cell death. The protection conferred by PI3K relies on the subsequent induction of Bcl-xL, a prosurvival member of the Bcl-2 protein family. In addition, EPO counteracts the upregulation of the pro-apoptotic BH3-only protein BIM, which is induced by serum withdrawal. EPO also activates extracellular signal-regulated kinase 1 and 2 (ERK1/2), which are involved in a Bcl-xL-independent cytoprotective pathway. EPO caused a prolonged activation of nuclear factor (NF)-κB, which was blocked by inhibition of PI3K, but not by inhibition of mitogen-activated protein (MAP)/ERK kinase (MEK), suggesting that EPO-activated NF-κB requires PI3K activity. However, the activation of the NF-κB pathway was not required for the ability of EPO to counteract endothelial apoptosis. Thus EPO promotes survival of endothelial cells through PI3K-dependent Bcl-xL-induction and BIM regulation, as well as through a separate mechanism involving the ERK pathway.

scholarly journals Acanthamoeba castellanii Induces Host Cell Death via a Phosphatidylinositol 3-Kinase-Dependent Mechanism

2005 ◽  
Vol 73 (5) ◽  
pp. 2704-2708 ◽  
Author(s):  
James Sissons ◽  
Kwang Sik Kim ◽  
Monique Stins ◽  
Samantha Jayasekera ◽  
Selwa Alsam ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Endothelial Cell ◽  
Acanthamoeba Castellanii ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Endothelial Cell Death ◽  
Microvascular Endothelial ◽  
Phosphatidylinositol 3

ABSTRACT Granulomatous amoebic encephalitis due to Acanthamoeba castellanii is a serious human infection with fatal consequences, but it is not clear how the circulating amoebae interact with the blood-brain barrier and transmigrate into the central nervous system. We studied the effects of an Acanthamoeba encephalitis isolate belonging to the T1 genotype on human brain microvascular endothelial cells, which constitute the blood-brain barrier. Using an apoptosis-specific enzyme-linked immunosorbent assay, we showed that Acanthamoeba induces programmed cell death in brain microvascular endothelial cells. Next, we observed that Acanthamoeba specifically activates phosphatidylinositol 3-kinase. Acanthamoeba-mediated brain endothelial cell death was abolished using LY294002, a phosphatidylinositol 3-kinase inhibitor. These results were further confirmed using brain microvascular endothelial cells expressing dominant negative forms of phosphatidylinositol 3-kinase. This is the first demonstration that Acanthamoeba-mediated brain microvascular endothelial cell death is dependent on phosphatidylinositol 3-kinase.

Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1–dependent activation of PI-3K/Akt and regulation of Bcl-2 family members

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3169-3177 ◽  
Author(s):  
Vidya Limaye ◽  
Xiaochun Li ◽  
Chris Hahn ◽  
Pu Xia ◽  
Michael C. Berndt ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Protein Kinase ◽  
Cell Survival ◽  
Phosphatidyl Inositol ◽  
B Cell Lymphoma ◽  
Sphingosine Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Sphingosine 1 Phosphate

AbstractSphingosine-1-phosphate (S1P), the bioactive product of sphingosine kinase (SK) activation, is a survival factor for endothelial cells. The mechanism of SK-mediated survival was investigated in endothelial cells with moderately raised intracellular SK activity. Overexpression of SK mediated survival primarily through the activation of the phosphatidyl inositol 3-kinase (PI-3K)/protein kinase B (Akt/PKB) pathway and an associated up-regulation of the antiapoptotic protein B cell lymphoma gene 2 (Bcl-2) and down-regulation of the proapoptotic protein bisindolylmaleimide (Bcl-2 interacting mediator of cell death; Bim). In addition there was an up-regulation and dephosphorylation of the junctional molecule platelet endothelial cell adhesion molecule-1 (PECAM-1), which was obligatory for activation of the PI-3K/Akt pathway, for SK-induced cell survival, and for the changes in the apoptosis-related proteins. Thus, raised intracellular SK activity induced a molecule involved in cell–cell interactions to augment cell survival through a PI-3K/Akt–dependent pathway. This is distinct from the activation of both PI-3K/Akt and mitogen-activated protein kinase (MAPK) pathways seen with exogenously added S1P. Cells overexpressing SK showed enhanced survival under conditions of serum deprivation and absence of attachment to extracellular matrix, suggesting a role for SK in the regulation of vascular phenomena that occur under conditions of stress, such as angiogenesis and survival in unattached states, as would be required for a circulating endothelial cell.

ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4407-4409 ◽  
Author(s):  
Amir Tadros ◽  
David P. Hughes ◽  
Benjamin J. Dunmore ◽  
Nicholas P. J. Brindle
Keyword(s):  
Cell Death ◽  
Endothelial Cell ◽  
Zinc Finger Protein ◽  
Nuclear Factor Κb ◽  
Phosphatidylinositol 3 Kinase ◽  
Endothelial Apoptosis ◽  
Growth Factor Deprivation ◽  
Endothelial Cell Death ◽  
Endothelial Receptor ◽  
Angiopoietin 1

AbstractA20 binding inhibitor of NF-κB activation-2, ABIN-2, is a newly identified intracellular protein that interacts with the zinc finger protein A20. ABIN-2 inhibits nuclear factor-κB (NF-κB) activity and is a possible effector of A20 regulation of NF-κB. Although A20 is a potent inhibitor of endothelial apoptosis, the effect of ABIN-2 on apoptosis is not known. ABIN-2 also interacts with the endothelial receptor Tie2. This receptor is essential for blood vessel formation and promotes endothelial survival. Here we examine the effects of ABIN-2 on endothelial cell apoptosis and its potential involvement in Tie2-mediated endothelial survival. ABIN-2 was found to inhibit endothelial apoptosis and rescue cells from death following growth factor deprivation. The inhibitors of phosphatidylinositol-3 kinase, wortmannin and LY294002, suppressed ABIN-2 inhibition of endothelial cell death. Deletion of the carboxy-terminus of ABIN-2 removed its ability to inhibit apoptosis. Expression of truncated ABIN-2 prevented the Tie2-activating ligand angiopoietin-1 from inhibiting endothelial cell death. (Blood. 2003;102:4407-4409)

scholarly journals Role of thromboxane in retinal microvascular degeneration in oxygen-induced retinopathy

2001 ◽  
Vol 90 (6) ◽  
pp. 2279-2288 ◽  
Author(s):  
Martin H. Beauchamp ◽  
Ana Katherine Martinez-Bermudez ◽  
Fernand Gobeil ◽  
Anne Marilise Marrache ◽  
Xin Hou ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Endothelial Cell ◽  
Oxidant Stress ◽  
Microvascular Endothelial Cell ◽  
Oxygen Induced Retinopathy ◽  
Rat Pups ◽  
Endothelial Cell Death ◽  
Peroxidation Product ◽  
Synthase Inhibitor

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.

Peptide5 attenuates rtPA related brain microvascular endothelial cells reperfusion injury via the Wnt/β-catenin signalling pathway

2021 ◽  
Vol 18 ◽  
Author(s):  
Weimin Ren ◽  
Chuyi Huang ◽  
Heling Chu ◽  
Yuping Tang ◽  
Xiaobo Yang
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Endothelial Cell ◽  
Cell Injury ◽  
Time Window ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Endothelial Cell Injury ◽  
Endothelial Cell Death ◽  
Therapeutic Time Window

Aims: Brain vascular endothelial cell dysfunction after rtPA treatment is a significant factor associated with poor prognosis, suggesting that alleviation of rtPA-related endothelial cell injury may represent a potential beneficial strategy along with rtPA thrombolysis. Background: Thrombolysis with recombinant tissue plasminogen activator (rtPA) is beneficial for acute ischemic stroke but may increase the risk of hemorrhagic transformation (HT), which is considered ischemia-reperfusion injury. The underlying reason may contribute to brain endothelial injury and dysfunction related to rtPA against ischemic stroke. As previous studies have demonstrated that transiently blocked Cx43 using peptide5 (Cx43 mimetic peptide) during retinal ischemia reduced vascular leakage, it is necessary to know whether this might help decrease side effect of rtPA within the therapeutic time window. Objective: This study aims to investigate the effects of peptide5 on rtPA-related cell injury during hypoxia/reoxygenation (H/R) within the therapeutic time window. Methods: In this study, we established a cell hypoxia/reoxygenation H/R model in cultured primary rat brain microvascular endothelial cells (RBMECs) and evaluated endothelial cell death and permeability after rtPA treatment with or without transient peptide5. In addition, we also investigated the potential signaling pathway to explore the underlying mechanisms preliminarily. Results: The results showed that peptide5 inhibited rtPA-related endothelial cell death and permeability. It also slightly increased tight junction (ZO-1, occluding, claudin-5) and β-catenin mRNA expression, demonstrating that peptide5 might attenuate endothelial cell injury by regulating the Wnt/β-catenin pathway. The following bioinformatic exploration from the GEO dataset GSE37239 was also consistent with our findings. Conclusion: This study showed that the application of peptide5 maintained cell viability and permeability associated with rtPA treatment, revealing a possible pathway that could be exploited to limit rtPA-related endothelial cell injury during ischemic stroke. Furthermore, the altered Wnt/β-catenin signaling pathway demonstrated that signaling pathways associated with Cx43 might have potential applications in the future. This study may provide a new way to attenuate HT and assist the application of rtPA in ischemic stroke.

Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature

2006 ◽  
Vol 291 (2) ◽  
pp. H517-H531 ◽  
Author(s):  
Anuradha Dhanasekaran ◽  
Rula Al-Saghir ◽  
Bernardo Lopez ◽  
Daling Zhu ◽  
David D. Gutterman ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Survival ◽  
Kinase Inhibitor ◽  
Protective Action ◽  
Underlying Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Epoxyeicosatrienoic Acids ◽  
Protective Effects ◽  
Human Coronary Artery ◽  
Mitogen Activated Protein

Epoxyeicosatrienoic acids (EETs) are cytochrome P-450 (CYP) metabolites synthesized from the essential fatty acid arachidonic acid to generate four regioisomers, 14,15-, 11,12-, 8,9-, and 5,6-EET. Cultured human coronary artery endothelial cells (HCAECs) contain endogenous EETs that are increased by stimulation with physiological agonists such as bradykinin. Because EETs are known to modulate a number of vascular functions, including angiogenesis, we tested each of the four regioisomers to characterize their effects on survival and apoptosis of HCAECs and cultured human lung microvascular endothelial cells (HLMVECs). A single application of physiologically relevant concentration of 14,15-, 11,12-, and 8,9-EET but not 5,6-EET (0.75–300 nM) promoted concentration-dependent increase in cell survival of HLMVECs and HCAECs after removal of serum. The lipids also protected the same cells from death via the intrinsic, as well as extrinsic, pathways of apoptosis. EETs did not increase intracellular calcium concentration ([Ca2+]i) or phosphorylate mitogen-activated protein kinase p44/42 when applied to these cells, and their protective action was attenuated by the phosphotidylinositol-3 kinase inhibitor wortmannin (10 μM) but not the cyclooxygenase inhibitor indomethacin (20 μM). Our results demonstrate for the first time the capacity of EETs to enhance human endothelial cell survival by inhibiting both the intrinsic, as well as extrinsic, pathways of apoptosis, an important underlying mechanism that may promote angiogenesis and endothelial survival during atherosclerosis and related cardiovascular ailments.

scholarly journals Kallistatin attenuates endothelial apoptosis through inhibition of oxidative stress and activation of Akt-eNOS signaling

2010 ◽  
Vol 299 (5) ◽  
pp. H1419-H1427 ◽  
Author(s):  
Bo Shen ◽  
Lin Gao ◽  
Yi-Te Hsu ◽  
Grant Bledsoe ◽  
Makato Hagiwara ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Oxygen Species ◽  
Phosphatidylinositol 3 Kinase ◽  
Reactive Oxygen Species Formation ◽  
Endothelial Apoptosis ◽  
Species Formation ◽  
Tnf Α

Kallistatin is a regulator of vascular homeostasis capable of controlling a wide spectrum of biological actions in the cardiovascular and renal systems. We previously reported that kallistatin inhibited intracellular reactive oxygen species formation in cultured cardiac and renal cells. The present study was aimed to investigate the role and mechanisms of kallistatin in protection against oxidative stress-induced vascular injury and endothelial cell apoptosis. We found that kallistatin gene delivery significantly attenuated aortic superoxide formation and glomerular capillary loss in hypertensive DOCA-salt rats. In cultured endothelial cells, kallistatin suppressed TNF-α-induced cellular apoptosis, and the effect was blocked by the pharmacological inhibition of phosphatidylinositol 3-kinase and nitric oxide synthase (NOS) and by the knockdown of endothelial NOS (eNOS) expression. The transduction of endothelial cells with adenovirus expressing dominant-negative Akt abolished the protective effect of kallistatin on endothelial apoptosis and caspase activity. In addition, kallistatin inhibited TNF-α-induced reactive oxygen species formation and NADPH oxidase activity, and these effects were attenuated by phosphatidylinositol 3-kinase and NOS inhibition. Kallistatin also prevented the induction of Bim protein and mRNA expression by oxidative stress. Moreover, the downregulation of forkhead box O 1 (FOXO1) and Bim expression suppressed TNF-α-mediated endothelial cell death. Furthermore, the antiapoptotic actions of kallistatin were accompanied by Akt-mediated FOXO1 and eNOS phosphorylation, as well as increased NOS activity. These findings indicate a novel role of kallistatin in the protection against vascular injury and oxidative stress-induced endothelial apoptosis via the activation of Akt-dependent eNOS signaling.

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