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      Apoptotic Phenotype Alters the Capacity of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand to Induce Human Vascular Endothelial Activation

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          Abstract

          Background/Aims: The ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to activate vascular endothelium is unclear. This study investigates the link between endothelial apoptosis and activation in response to TRAIL. Methods and Results: Endothelial cell apoptosis was modeled with the immortalized human endothelial cell line EA.hy926, and with primary human umbilical vein endothelial cells (HUVEC) sensitized with the phosphatidylinositol 3-kinase inhibitor LY294002 in 1% serum. EA.hy926 expressed greatest levels of TRAIL receptors R1 and R2, and HUVEC of R2 and R3, determined by flow cytometry. Recombinant human (rh)TRAIL induced apoptosis in both models, reducing cell numbers preventable with caspase inhibitors, and confirmed by annexin V staining. In EA.hy926, rhTRAIL activated NF-ĸB (1 h) with increased ICAM-1 expression (24 h). rhTRAIL also increased adhesion of human neutrophils, blocked with an antibody to neutrophil CD18, a ligand for ICAM-1, and with antibodies to TRAIL and TRAIL-R1 and R2. rhTRAIL increased neutrophil adhesion to sensitized HUVEC, without effect on unmodified HUVEC. rhTRAIL did not increase surface labeling of ICAM-1 or E-selectin in sensitized HUVEC. Conclusions: TRAIL increases neutrophil adhesion when it concurrently induces apoptosis both in EA.hy926 and in sensitized HUVEC. TRAIL may therefore induce endothelial activation in concert with endothelial apoptosis.

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          Most cited references 32

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          A novel assay for apoptosis Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V

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            Role of Akt signaling in vascular homeostasis and angiogenesis.

            Akt is a serine/threonine protein kinase that is activated by a number of growth factors and cytokines in a phosphatidylinositol-3 kinase-dependent manner. Although antiapoptotic activity of Akt is well known, it also regulates other aspects of cellular functions, including migration, glucose metabolism, and protein synthesis. In this review, Akt signaling in endothelial cells and its critical roles in the regulation of vascular homeostasis and angiogenesis will be discussed.
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              FLICE is activated by association with the CD95 death-inducing signaling complex (DISC).

              Upon activation, the apoptosis-inducing cell membrane receptor CD95 (APO-1/Fas) recruits a set of intracellular signaling proteins (CAP1-4) into a death-inducing signaling complex (DISC). In the DISC, CAP1 and CAP2 represent FADD/MORT1. CAP4 was identified recently as an ICE-like protease, FLICE, with two death effector domains (DED). Here we show that FLICE binds to FADD through its N-terminal DED. This is an obligatory step in CD95 signaling detected in the DISC of all CD95-sensitive cells tested. Upon prolonged triggering of CD95 with agonistic antibodies all cytosolic FLICE gets proteolytically activated. Physiological FLICE cleavage requires association with the DISC and occurs by a two-step mechanism. Initial cleavage generates a p43 and a p12 fragment further processed to a p10 fragment. Subsequent cleavage of the receptor-bound p43 results in formation of the prodomain p26 and the release of the active site-containing fragment p18. Activation of FLICE is blocked by the peptide inhibitors zVAD-fmk, zDEVD-fmk and zIETD-fmk, but not by crmA or Ac-YVAD-CHO. Taken together, our data indicate that FLICE is the first in a cascade of ICE-like proteases activated by CD95 and that this activation requires a functional CD95 DISC.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2008
                February 2008
                16 October 2007
                : 45
                : 2
                : 111-122
                Affiliations
                Departments of aPathology, and bMicrobiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
                Article
                109880 J Vasc Res 2008;45:111–122
                10.1159/000109880
                17940338
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 8, References: 47, Pages: 12
                Categories
                Research Paper

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