The antiapoptotic effect of heme oxygenase-1 in endothelial cells involves the degradation of p38 alpha MAPK isoform.
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 p38alpha and p38beta MAPKs was inhibited by the pyridinyl imidazole SB202190. Using small interfering RNA, p38beta was found to be cytoprotective in EC, whereas p38alpha was not. When overexpressed in EC, HO-1 targeted specifically the p38alpha but not the p38beta MAPK isoform for degradation by the 26S proteasome, an effect reversed by the 26S proteasome inhibitors MG-132 or lactacystin. Inhibition of p38alpha expression was also observed when HO-1 was induced physiologically by iron protoporphyrin IX (hemin). Inhibition of p38alpha no longer occurred when HO activity was inhibited by tin protoporphyrin IX, suggesting that p38alpha degradation was mediated by an end product of heme catabolism. Exogenous CO inhibited p38alpha expression in EC, suggesting that CO is the end product that mediates this effect. The antiapoptotic effect of HO-1 was impaired when p38alpha 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 p38beta expression was targeted by a specific p38beta small interfering RNA. In conclusion, the antiapoptotic effect of HO-1 in EC is dependent on the degradation of p38alpha by the 26S proteasome and on the expression of p38beta.
Silva
Gabriela
G
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Cunha
Andreia
A
Grégoire
Isabel Pombo
IP
Seldon
Mark P
MP
Soares
Miguel P
MP
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002248:Carbon Monoxide / Q000502:physiology; D002417:Cattle; D002460:Cell Line; D019610:Cytoprotection / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology*; D004789:Enzyme Activation / Q000502:physiology; D006367:HeLa Cells; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D048290:Mitogen-Activated Protein Kinase 11 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; D007527:Isoenzymes; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease