Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis

Heme oxygenase 1 (HO-1) inhibits apoptosis by regulating cellular prooxidan t iron. We now show that there is an additional mechanism by which HO-1 inh ibits apoptosis, namely by generating the gaseous molecule carbon monoxide (CO). Overexpression of HO-1, or induction of HO-1 expression by heme, prot ects endothelial cells (ECs) from apoptosis. When HO-1 enzymatic activity i s blocked by tin protoporphyrin (SnPPIX) or the action of CO is inhibited b y hemoglobin (Hb), HO-1 no longer prevents EC apoptosis while these reagent s do not affect the antiapoptotic action of bcl-2, Exposure of ECs to exoge nous CO, under inhibition of HO-1 activity by SnPPIX, substitutes HO-1 in p reventing EC apoptosis. The mechanism of action of HO-1/CO is dependent on the activation of the p38 mitogen-activated protein kinase (MAPK) si,signal ing transduction pathway. Expression of HO-1 or exposure of ECs to exogenou s CO enhanced p38 MAPK activation by TNF-alpha. Specific inhibition of p38 MAPK activation by the pyridinyl imidazol SB203580 or through overexpressio n of a p38 MAPK dominant negative mutant abrogated the antiapoptotic effect of HO-1. Taken together, these data demonstrate that the antiapoptotic eff ect of HO-1 in ECs is mediated by CO and more specifically via the activati on of p38 MAPK by CO.