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.
Carbon Monoxide Generated by Heme Oxygenase 1 Suppresses Endothelial Cell Apoptosis
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; Mφ, monocyte/macrophage(s); ppm, parts per million; SnPPIX, tin protoporphyrin; VASP, vasodilatator-stimulated phosphoprotein.
Sophie Brouard, Leo E. Otterbein, Josef Anrather, Edda Tobiasch, Fritz H. Bach, Augustine M.K. Choi, Miguel P. Soares; Carbon Monoxide Generated by Heme Oxygenase 1 Suppresses Endothelial Cell Apoptosis. J Exp Med 2 October 2000; 192 (7): 1015–1026. doi: https://doi.org/10.1084/jem.192.7.1015
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