Carbon Monoxide Generated by Heme Oxygenase 1 Suppresses Endothelial Cell Apoptosis

By S. Brouard, L. Otterbein, J. Anrather, E. Tobiasch, F. Bach, A. Choi, M. Soares. Journal of Experimental Medicine, 2000

1,048 citations recorded by the source corpus.

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-α. 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.

Subfields: Cell Biology, Molecular Biology, Pediatrics, Perinatology and Child Health

View Paper: https://www.semanticscholar.org/paper/138b0559089bbd850837990e1a23e18ff09aa965

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In Molecular Biology

1. Rui Wang
2. R. Stocker
3. Lingyun Wu
4. S. Ryter
5. A. Choi
6. J. Alam
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In Pediatrics, Perinatology and Child Health

1. Rui Wang
2. A. Kappas
3. Nader G. Abraham

Citations in the corpus

• Mechanisms of cell protection by heme oxygenase-1. (2010, background): “The subsequent finding that when applied exogenously to endothelial cells in vitro, CO can mimic the cytoprotective effect of HO-1 (78) (Figure 3) led to the notion that the cytoprotective effect of HO-1 is mediated via the production of CO.”
• Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications (2005, background): “It should be pointed out that precise time course for upregulation of HO-1 leading to acute production of CO and target response has not been determined.”
• Role of oxidative modifications in atherosclerosis. (2004, background): “Heme oxygenase-derived carbon monoxide has been implicated in this process (685), as well as other potentially protective activities such as endothelium-dependent relaxation (1099) and inhibition of apoptosis of endothelial cells (96, 863).”
• Heme oxygenase-1: from bench to bedside. (2005, background): “The anti-apoptotic action of CO has also been shown to involve the p38 MAPK system (18).”
• Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. (2006, background): “In the endothelial cell model, the inhibitory effect of CO on TNF- -induced apoptosis could be abolished with the selective chemical inhibitor SB203580 or a p38 MAPK dominant negative mutant, implying a critical role for the p38 MAPK pathway (70).”