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

Circ Res. 2007 Oct 26;101(9):919-27. doi: 10.1161/CIRCRESAHA.107.154781. Epub 2007 Sep 6.

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 2alpha 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 glucose-regulated 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / metabolism
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Carbon Monoxide / metabolism*
  • Carbon Monoxide / pharmacology
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum / enzymology
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology*
  • Enzyme Induction / drug effects
  • Enzyme Induction / physiology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • NF-E2-Related Factor 2 / metabolism
  • Nuclear Proteins / metabolism
  • Oxidative Stress / physiology
  • RNA, Small Interfering
  • Regulatory Factor X Transcription Factors
  • Transcription Factor CHOP / genetics
  • Transcription Factors
  • Umbilical Veins / cytology
  • eIF-2 Kinase / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • DDIT3 protein, human
  • DNA-Binding Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nuclear Proteins
  • RNA, Small Interfering
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • Transcription Factor CHOP
  • Carbon Monoxide
  • Heme Oxygenase-1
  • PERK kinase
  • eIF-2 Kinase
  • p38 Mitogen-Activated Protein Kinases