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

Abstract

Abstract-Carbon monoxide (CO), a reaction product of the cytoprotective heme oxygenase (HO)-1, is antiapoptotic 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 2␣ and the expression of activating transcription factor 4. However, CO fails to induce X-box binding protein-1 expression and activating transcription factor 6 cleavage. CO had no significant effect on synthesis of endoplasmic reticulum (ER) chaperone proteins such as the 78-kDa glucoseregulated proteins 78 and 94. Instead, CO prevented X-box binding protein 1 expression and activating transcription factor 6 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 expression, which was associated with its activation of p38 mitogen-activated protein kinase. Similarly, endogenous CO produced from endothelial HO-1 induced by either exogenous CO or a pharmacological inducer was also cytoprotective against ER stress through C/EBP homologous protein suppression. Our findings suggest that CO renders endothelial cells resistant to ER stress not only by downregulating C/EBP homologous protein expression via p38 mitogen-activated protein kinase activation but also by upregulating 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.

Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity

“…We also report that similarly to chemical chaperone PBA, the induction of HO-1 by CoPP, reversed the effects of high glucose on ER stress indicating an important cross talk between ROS and ER stress in these conditions. Consistent with our observations, Kim et al [33] have reported that that induction of HO-1 through the exposure of HUVECs to CO or CoPP prevented thapsigargin-induced expression of CHOP [33].…”

Involvement of endoplasmic reticulum stress in adenosine-induced human hepatoma HepG2 cell apoptosis

“…translocation of cHop from the cytoplasm to the nucleus could regulate the expression of ERS-related genes (17,43). Furthermore, it has been demonstrated that cHop gene inhibition by drugs or knockout can protect cells from apoptosis mediated by ers (41,42). previous studies have demonstrated that cHop-regulated genes, such as Dr5 (44), TRB3 (45) and bcl-2 (46), are involved in the cytoplasm to the nucleus was also observed (Fig.…”

Regulación de hemooxigenasa e indoleamina por citocinas en células de cáncer cervicouterino y actividad citotóxica de células natural killer

“…Se ha reportado la sobreexpresión de HO-1 e IDO en diferentes tipos de cáncer, incluido el cáncer cervicouterino 20,25,26 . Los mecanismos de regulación de estas enzimas van desde factores de transcripción, activados por estímulos externos, hasta los productos de la actividad de las enzimas 27 . La expresión de IDO en respuesta a citocinas es dependiente del tipo celular 28 , igual que HO-1.…”