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MAPK Isoform1
Instituto Gulbenkian de Ciência, Oeiras, Portugal
Heme oxygenase-1 (HO-1) protects endothelial cells (EC) from undergoing apoptosis. This effect is mimicked by CO, generated via the catabolism of heme by HO-1. The antiapoptotic effect of CO in EC was abrogated when activation of the p38
and p38
MAPKs was inhibited by the pyridinyl imidazole SB202190. Using small interfering RNA, p38 was found to be cytoprotective in EC, whereas p38 was not. When overexpressed in EC, HO-1 targeted specifically the p38 but not the p38 MAPK isoform for degradation by the 26S proteasome, an effect reversed by the 26S proteasome inhibitors MG-132 or lactacystin. Inhibition of p38 expression was also observed when HO-1 was induced physiologically by iron protoporphyrin IX (hemin). Inhibition of p38 no longer occurred when HO activity was inhibited by tin protoporphyrin IX, suggesting that p38 degradation was mediated by an end product of heme catabolism. Exogenous CO inhibited p38 expression in EC, suggesting that CO is the end product that mediates this effect. The antiapoptotic effect of HO-1 was impaired when p38 expression was restored ectopically or when its degradation by the 26S proteasome was inhibited by MG-132. Furthermore, the antiapoptotic effect of HO-1 was lost when p38 expression was targeted by a specific p38 small interfering RNA. In conclusion, the antiapoptotic effect of HO-1 in EC is dependent on the degradation of p38 by the 26S proteasome and on the expression of p38.
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