Carbon Monoxide Induces Heme Oxygenase-1 Via Activation Of Protein Kinase R-like Endoplasmic Reticulum Kinase And Inhibits Endothelial Cell Apoptosis Triggered By Endoplasmic Reticulum Stress

Carbon monoxide (CO), a reaction product of the cytoprotective heme oxygenase (HO)-1, is anti-apoptotic in a variety of models of cellular injury, but the precise mechanisms remain to be established. In human umbilical vein endothelial cells, exogenous CO activated Nrf2 through the phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK), resulting in HO-1 expression. CO-induced activation of PERK was followed by the phosphorylation of eukaryotic translation initiation factor 2a (eIF2a) and the expression of activating transcription factor 4 (ATF4). However, CO fails to induce X-box binding protein 1 (Xbp-1) expression and ATF6 cleavage. CO had no significant effect on synthesis of endoplasmic reticulum (ER) chaperone proteins such as 78-kDa glucose-regulated protein (GRP78) and GRP94. Instead, CO prevented Xbp-1 expression and ATF6 cleavage induced by ER stress inducers such as thapsigargin, tunicamycin and homocysteine. CO also prevented endothelial apoptosis triggered by these ER inducers through suppression of C/EBP homologous protein (CHOP) expression, which was associated with its activation of p38 mitogen-activated protein kinase (MAPK). Similarly, endogenous CO produced from endothelial HO-1 induced by either exogenous CO or a pharmacological inducer was also cytoprotective against ER stress through the suppression of CHOP. CO renders endothelial cells resistant to ER stress not only by down-regulating CHOP expression via p38 MAPK activation but also by up-regulating Nrf2-dependent HO-1 expression via PERK activation. Thus, the HO-1/CO system might be potential therapeutics in vascular diseases associated with ER stress.