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

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.

Hypochlorous acid-induced heme oxygenase-1 gene expression promotes human endothelial cell survival

“…Previous studies identified oxidized low-density lipoprotein, peroxynitrite, homocysteine, and inflammatory cytokines as potent inducers of HO-1 (3,8,11,12,30). Furthermore, growth factors such as plateletderived growth factor, transforming growth factor-␤, and angiotensin II, which are present in vascular lesions, are also able to upregulate HO-1 expression (17).…”

“…Furthermore, growth factors such as plateletderived growth factor, transforming growth factor-␤, and angiotensin II, which are present in vascular lesions, are also able to upregulate HO-1 expression (17). Interestingly, the induction of HO-1 by HOCl and several atherogenic factors is mediated through the activation of Nrf2 (3,12,30). However, the upstream signaling pathways that lead to the activation of Nrf2 may differ between stimuli.…”

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

“…c-Jun can form part of the AP-1, StRE [31], and EpRE binding complexes [64] and further, StRE-and EpRE-mediated induction of HO-1 has been shown previously in rat cell lines [31,64,65]. Although no change in total EpRE binding was observed in response to HNE, the EpRE and/ or StRE enhancer elements could still be involved in the increase in HO-1 mRNA via transcription factor complex remodeling [39], specifically through activated c-Jun joining the complex and potentially displacing an inhibitor [66].…”

Heme Oxygenase-1

“…More recently, it has been reported that in cultured vascular smooth muscle cells, endoplasmic reticulum stress increased HO-1 mRNA and protein via the ARE, and this was associated with cell survival. 49 The "endoplasmic reticulum stress response" constitutes a general response to endoplasmic reticulum-associated stress such as unfolded proteins, glucose starvation, and disruption of intracellular calcium homeostasis. Endoplasmic reticulum-initiated cell death pathways are increasingly recognized as playing important roles in several diseases, including ischemia/reperfusion injury, heart disease, and diabetes.…”