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.
Highlights
Heme oxygenase-1 (HO-1) is a cytoprotective protein that catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide (CO)
The other HO-1 products failed to block apoptosis or GADD153 expression during endoplasmic reticulum (ER) stress. These results demonstrated that ER stress is an inducer of HO-1 gene expression in vascular smooth muscle cells (SMC) and that HO-1-derived CO acts in an autocrine fashion to inhibit SMC apoptosis
We identified ER stress as a novel inducer of HO-1 gene expression in vascular SMC
Summary
Heme oxygenase-1 (HO-1) is a cytoprotective protein that catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide (CO). 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). Three ER-resident transmembrane proteins, the kinase and endoribonuclease IRE1, the PERK kinase, and the basic leucine-zipper transcription factor ATF6, have been identified as proximal sensors of ER stress [23] Activation of these sensors results in the up-regulation of genes encoding ER chaperone proteins such as GRP78 that increase protein folding activity and prevent protein aggregation. When ER function is severely impaired, apoptosis is induced This apoptotic event is triggered by the activation of the proapoptotic transcription factor GADD153 and/or by the activation of ER-associated caspase-12 (24 –26). The activation of the HO-1 gene by ER stress does not occur via the
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