The Journal of Experimental Medicine
ELISpot, FluoroSpot and ELISA kits from Mabtech
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published online 2 October 2000.
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 452K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Brouard, S.
Right arrow Articles by Soares, M. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brouard, S.
Right arrow Articles by Soares, M. P.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?
© The Rockefeller University Press, 0022-1007/2000/10/1015/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 7, October 2, 2000 1015-1026

Original Article

Carbon Monoxide Generated by Heme Oxygenase 1 Suppresses Endothelial Cell Apoptosis

Sophie Brouarda, Leo E. Otterbeinb, Josef Anratherc, Edda Tobiascha, Fritz H. Bacha, Augustine M.K. Choib, and Miguel P. Soaresa

a Immunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215
b Department of Internal Medicine, Pulmonary and Critical Care Section, Yale University, School of Medicine, New Haven, Connecticut 06520
c Department of Neurobiology, Weill Medical College of Cornell University, New York, New York 10021
Immunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave., Boston, MA 02215.617-632-0880617-632-0885

Heme oxygenase 1 (HO-1) inhibits apoptosis by regulating cellular prooxidant iron. We now show that there is an additional mechanism by which HO-1 inhibits apoptosis, namely by generating the gaseous molecule carbon monoxide (CO). Overexpression of HO-1, or induction of HO-1 expression by heme, protects endothelial cells (ECs) from apoptosis. When HO-1 enzymatic activity is blocked by tin protoporphyrin (SnPPIX) or the action of CO is inhibited by hemoglobin (Hb), HO-1 no longer prevents EC apoptosis while these reagents do not affect the antiapoptotic action of bcl-2. Exposure of ECs to exogenous CO, under inhibition of HO-1 activity by SnPPIX, substitutes HO-1 in preventing EC apoptosis. The mechanism of action of HO-1/CO is dependent on the activation of the p38 mitogen-activated protein kinase (MAPK) signaling transduction pathway. Expression of HO-1 or exposure of ECs to exogenous CO enhanced p38 MAPK activation by TNF-{alpha}. Specific inhibition of p38 MAPK activation by the pyridinyl imidazol SB203580 or through overexpression of a p38 MAPK dominant negative mutant abrogated the antiapoptotic effect of HO-1. Taken together, these data demonstrate that the antiapoptotic effect of HO-1 in ECs is mediated by CO and more specifically via the activation of p38 MAPK by CO.

Key Words: apoptosis • endothelial cells • heme oxygenase 1 • carbon monoxide • p38 mitogen-activated protein kinase

A.M.K. Choi and M.P. Soares contributed equally to this work.

Abbreviations used in this paper: Act.D, actinomycin D; BAEC, bovine aortic endothelial cell; CoPPIX, cobalt protoporphyrin; DFO, deferoxamine mesylate; EC, endothelial cell; ERK, extracellular signal–regulated kinase; FePP, iron protoporphyrin; GFP, green fluorescent protein; Hb, hemoglobin; HO-1, heme oxygenase 1; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; M{varphi}, monocyte/macrophage(s); ppm, parts per million; SnPPIX, tin protoporphyrin; VASP, vasodilatator-stimulated phosphoprotein.

© 2000 The Rockefeller University Press


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?




  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS