The Antiapoptotic Effect of Heme Oxygenase-1 in Endothelial Cells Involves the Degradation of p38α MAPK Isoform

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Abstract
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 p38α and p38β MAPKs was inhibited by the pyridinyl imidazole SB202190. Using small interfering RNA, p38β was found to be cytoprotective in EC, whereas p38α was not. When overexpressed in EC, HO-1 targeted specifically the p38α but not the p38β MAPK isoform for degradation by the 26S proteasome, an effect reversed by the 26S proteasome inhibitors MG-132 or lactacystin. Inhibition of p38α expression was also observed when HO-1 was induced physiologically by iron protoporphyrin IX (hemin). Inhibition of p38α no longer occurred when HO activity was inhibited by tin protoporphyrin IX, suggesting that p38α degradation was mediated by an end product of heme catabolism. Exogenous CO inhibited p38α expression in EC, suggesting that CO is the end product that mediates this effect. The antiapoptotic effect of HO-1 was impaired when p38α 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 p38β expression was targeted by a specific p38β small interfering RNA. In conclusion, the antiapoptotic effect of HO-1 in EC is dependent on the degradation of p38α by the 26S proteasome and on the expression of p38β.