Exogenous BH4/Bcl-2 Peptide Reverts Coronary Endothelial Cell Apoptosis Induced by Oxidative StressCantara S.a · Donnini S.a · Giachetti A.a,b · Thorpe P.E.c · Ziche M.a
aPharmacology Section, Department of Molecular Biology, University of Siena, Siena, and bLifetech s.r.l., Florence, Italy; cDepartment of Pharmacology and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Tex., USA
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
Background: Vascular endothelium undergoes apoptosis when exposed to reactive oxygen species (ROS), including hydrogen peroxide and superoxide radicals. ROS are believed to be the cause of damage to small vessels during ischemia-reperfusion injury and of arterial damage during atherosclerosis. Hydrogen peroxide-induced apoptosis is mediated through the inhibition of Bcl-xl activity and caspase-3 and caspase-9 activation. The BH4 domain of the Bcl-2 family members is responsible for their antiapoptotic activity. The BH4 domains of Bcl-2 and Bcl-xl inhibit cytochrome c release and the loss of mitochondrial membrane potential. Methods and Results: The purpose of this project was to study the antiapoptotic effect of cell-permeant derivative of Bcl-2 (BH4 peptide) on endothelial cells exposed to stress conditions. BH4 peptide was conjugated to the cell-permeable peptide TAT and was applied to endothelial cells under conditions of serum starvation and hydrogen peroxide treatment. TAT-BH4 reduced caspase-3 activity and prevented apoptotic cell death. Conclusion: Our results indicate that TAT-BH4 peptide can protect endothelial cells from ROS-induced apoptosis.
© 2004 S. Karger AG, Basel
- Wolin MS, Gupte SA, Oeckler RA: Superoxide in the vascular system. J Vasc Res 2002;39:191–207.
- Kunsch C, Medford RM: Oxidative stress as a regulator of gene expression in the vasculature. Circ Res 1999;85:753–766.
- Irani K: Oxidant signaling in vascular cell growth, death and survival. A review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling. Circ Res 2000;87:179–183.
- Lai JC, Tranfield EM, Walker DC, Dyck J, Kerjner A, Loo S, English D, Wong D, McDonald PC, Moghadasian MH, Wilson JE, McManus BM: Ultrastructural evidence of early endothelial damage in coronary arteries of rat cardiac allografts. J Heart Lung Transplant 2003;22:993–1004.
- Marsden VS, O’Connor L, O’Reilly LA, Silke J, Metcalf D, Erkt GP, Huang DCS, Cecconi F, Kuida K, Tomaselli KJ, Roy S, Nicholson DW, Vaux DL, Bouillet P, Adams JM, Strasser A: Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome. Nature 2002;419:634–637.
- Bradichani AZ, Stroka DM, Bilbao G, Curiel DT, Bach FH, Ferran C: Bcl-2 and Bcl-xl serve an anti-inflammatory function in endothelial cells through inhibition of NF-kB. J Clin Invest 1999;103:543–553.
- Shimizu S, Konishi A, Kodama T, Tsujimoto Y: BH4 domain of anti-apoptotic Bcl-2 family members closes voltage-dependent anion channel and inhibits apoptotic mitochondrial changes and cell death. Proc Natl Acad Sci USA 2000;97:3100–3105.
- Katakam PVG, Hoenig M, Ujhelyi MR, Miller AW: Cytochrome P450 activity and endothelial dysfunction in insulin resistance. J Vasc Res 2000;37:417–425.
- Denis GV, Yu Q, Ma P, Deeds L, Faller DV, Chen CY: Bcl-2, via its BH4 domain, blocks apoptotic signaling mediated by mitochondrial Ras. J Biol Chem 2003;278:5775–5785.
- Ziche M, Parenti A, Ledda F, Dell’Era P, Granger H, Maggi C, Presta M: Nitric oxide promotes proliferation and plasminogen activator production by coronary venular endothelium through endogenous bFGF. Circ Res 1997;80:845–852.
Morbidelli L, Orlando C, Maggi CA, Ledda F, Ziche M: Proliferation and migration of endothelial cells is promoted by endothelins via activation of ETB receptors. Am J Physiol 1995;269:686–695.
- Kroll J, Waltenberger J: A novel function of VEGF receptor-2 (KDR): Rapid release of nitric oxide in response to VEGF-A stimulation in endothelial cells. Biochem Biophys Res Commun 1999;265:636–639.
- Van Bruggen N, Thibodeaux H, Palmer JT, Lee WP, Fu L, Cairns B, Tumas D, Gerlai R, Williams SP, Van Looker Campagne M, Ferrara N: VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 1999;104:1613–1620.
- Shimizu S, Eguchi Y, Kosaka H, Kamiike W, Matsuda H, Tsujimoto Y: Prevention of hypoxia-induced cell death by Bcl-2 and Bcl-xl. Nature 1995;374:811–813.
- Gottlieb E, Vander Heiden MG, Thompson CB: Bcl-x(L) prevents the initial decrease in mitochondrial membrane potential and subsequent reactive oxygen species production during tumor necrosis factor alpha-induced apoptosis. Mol Cell Biol 2000;20:5680–5689.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: 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.