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J. Biol. Chem., Vol. 280, Issue 2, 872-877, January 14, 2005

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Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

ROLE IN CELL SURVIVAL^*

Xiao-ming Liu, Kelly J. Peyton, Diana Ensenat, Hong Wang, Andrew I. Schafer, Jawed Alam¶, and William Durante||**

From the Houston Veterans Affairs Medical Center and the Departments of Medicine and ^||Pharmacology, Baylor College of Medicine, Houston, Texas 77030, the Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and the ^¶Department of Molecular Genetics, Ochsner Clinic Foundation, New Orleans, Louisiana 70121

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.

Received for publication, September 10, 2004 , and in revised form, November 3, 2004.

^* This work was supported by National Institutes of Health Grants HL59976, HL36045, and HL62467 and by a grant from the American Heart Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** An Established Investigator of the American Heart Association. To whom correspondence should be addressed: Houston VA Medical Center, Rm. 130, Bldg. 109, 2002 Holcombe Blvd., Houston, TX 77030. Tel.: 713-791-1414 (ext. 5824); Fax: 713-794-7165; E-mail: wdurante{at}bcm.tmc.edu.

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