1: J Biol Chem. 2005 Jan 14;280(2):872-7. Epub 2004 Nov 16. 

Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in
vascular smooth muscle. Role in cell survival.

Liu XM, Peyton KJ, Ensenat D, Wang H, Schafer AI, Alam J, Durante W.

Houston Veterans Affairs Medical Center and the Department of Medicine, Baylor
College of Medicine, Houston, Texas 77030, USA.

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.

PMID: 15546873 [PubMed - indexed for MEDLINE]