title: Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in vascular smooth muscle. Role in cell survival.
abstract: Heme oxygenase-1 (HO-1) is a cytoprotective protein that catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide (CO). In the present study, we found that endoplasmic reticulum (ER) stress induced by a variety of experimental agents stimulated a time- and concentration-dependent increase in HO-1 mRNA and protein in vascular smooth muscle cells (SMC). The induction of HO-1 by ER stress was blocked by actinomycin D or cycloheximide and was independent of any changes in HO-1 mRNA stability. Luciferase reporter assays indicated that ER stress stimulated HO-1 promoter activity via the antioxidant response element. Moreover, ER stress induced the nuclear import of Nrf2 and the binding of Nrf2 to the HO-1 antioxidant response element. Interestingly, ER stress stimulated SMC apoptosis, as demonstrated by annexin V binding, caspase-3 activation, and DNA laddering. The induction of apoptosis by ER stress was potentiated by HO inhibition, whereas it was prevented by addition of HO substrate. In addition, exposure of SMC to exogenously administered CO inhibited ER stress-mediated apoptosis, and this was associated with a decrease in the expression of the proapoptotic protein, GADD153. In contrast, the other HO-1 products failed to block apoptosis or GADD153 expression during ER stress. These results demonstrated that ER stress is an inducer of HO-1 gene expression in vascular SMC and that HO-1-derived CO acts in an autocrine fashion to inhibit SMC apoptosis. The capacity of ER stress to stimulate the HO-1/CO system provides a novel mechanism by which this organelle regulates cell survival.
authors.affiliation: Houston Veterans Affairs Medical Center and the Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Xiao-ming
authors.initials: XM
authors.lastname: Liu
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Peyton
authors.forename: Diana
authors.initials: D
authors.lastname: Ensenat
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Schafer
authors.forename: Jawed
authors.initials: J
authors.lastname: Alam
authors.forename: William
authors.initials: W
authors.lastname: Durante
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020126:Brefeldin A / Q000494:pharmacology; D002248:Carbon Monoxide / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004790:Enzyme Induction / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006710:Homocysteine / Q000494:pharmacology; D018832:Molecular Chaperones / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D020218:Response Elements / Q000235:genetics
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D006710:Homocysteine; D020126:Brefeldin A; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1