Carbon monoxide protects against hyperoxia-induced endothelial cell apoptosis by inhibiting reactive oxygen species formation
Authors: Hong Pyo Kim
Augustine M K Choi
Yong Wang
Kiichi Nakahira
Xue Wang
Stefan W Ryter
Journal: Journal of Biological Chemistry (2007)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Hyperoxia; cell death; apoptosis; necrosis; reactive oxygen species
Affiliations: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.

Abstract:  Hyperoxia causes cell injury and death associated with reactive oxygen species formation and inflammatory responses. Recent studies show that hyperoxia-induced cell death involves apoptosis, necrosis, or mixed phenotypes depending on cell type, although the underlying mechanisms remain unclear. Using murine lung endothelial cells, we found that hyperoxia caused cell death by apoptosis involving both extrinsic (Fas-dependent) and intrinsic (mitochondria-dependent) pathways. Hyperoxia-dependent activation of the extrinsic apoptosis pathway and formation of the death-inducing signaling complex required NADPH oxidase-dependent reactive oxygen species production, because this process was attenuated by chemical inhibition, as well as by genetic deletion of the p47(phox) subunit, of the oxidase. Overexpression of heme oxygenase-1 prevented hyperoxia-induced cell death and cytochrome c release. Likewise, carbon monoxide, at low concentrations, markedly inhibited hyperoxia-induced endothelial cell death by inhibiting cytochrome c release and caspase-9/3 activation. Carbon monoxide, by attenuating hyperoxia-induced reactive oxygen species production, inhibited extrinsic apoptosis signaling initiated by death-inducing signal complex trafficking from the Golgi apparatus to the plasma membrane and downstream activation of caspase-8. We also found that carbon monoxide inhibited the hyperoxia-induced activation of Bcl-2-related proteins involved in both intrinsic and extrinsic apoptotic signaling. Carbon monoxide inhibited the activation of Bid and the expression and mitochondrial translocation of Bax, whereas promoted Bcl-X(L)/Bax interaction and increased Bad phosphorylation. We also show that carbon monoxide promoted an interaction of heme oxygenase-1 with Bax. These results define novel mechanisms underlying the antiapoptotic effects of carbon monoxide during hyperoxic stress. 

Retracted: No

PubPeer comments:
 https: doi.org 10.1016 j.immuni.2009.04.001 The authors have agreed to retract this paper because of duplication of the flow cytometry dot plots in Figure 1 (labeled as 3A9 +, 3A9 lpr and 3A9 gld) by the first author. This figure shows TCR and the CD4 and CD8 coreceptor expression in cells expressing a single TCR (3A9) on the lpr or gld background, which is important for establishing that TCR and coreceptor expression is not perturbed by the abnormalities in Fas or Fas ligand. This matter was investigated by Harvard Medical School and Brigham and Women s Hospital, as well as the Office of Research Integrity at the United States Department of Human Services, which found the first author to be responsible for the scientific misconduct pertaining to the issue described here. The authors stand by the validity of the other figures and sincerely apologize for the inconvenience caused by this retraction. ,