Redox regulation of heme oxygenase-1 expression during oxidant stress.

摘要

A deficiency in the micronutrient, selenium (Se), in endothelial cells (EC) results in numerous physiological changes that predispose the vascular microenvironment to oxidant stress and the development of oxidant stress-based diseases such as atherosclerosis. One way that Se protects cells from the damaging effects of oxidant stress is through the increase in the activity of selenoprotein antioxidants such as glutathione peroxidase and thioredoxin reductase (TrxR1). Therefore, reduced selenoprotein activity during dietary Se deficiency causes an accumulation of reactive oxygen species, as well as alterations in the redox status of certain signaling proteins modulating gene responses. The expression of protective antioxidants in EC can help to prevent the development of oxidant stress and therefore combat oxidative injury. Recent studies have demonstrated an upregulation in the antioxidant, heme oxygenase-1 (HO-1) during Se deficiency, suggesting the existence of an alternative source of host defenses during times of depleted selenoprotein activity. However, there remains a positive correlation between vascular dysfunction and Se deficiency, indicating that the compensatory increase in HO-1 is not sufficient to protect against oxidant stress in this microenvironment. This study demonstrates that the selenoprotein, TrxR1, is involved in the induction of protective antioxidant gene responses during oxidant stress. During Se deficiency, the decrease in the activity of TrxR1 and its substrate, thioredoxin (Trx), negatively influences the induction of HO-1 following exposure to the fatty acid hydroperoxide from the 15-lipoxygenase-1 (15-LOX-1) pathway, 15-hydroperoxy eicosatetraenoic acid (15-HPETE). The mechanism of TrxR1 mediated regulation of HO-1 expression occurs through alterations in the activation status of redox sensitive protein kinase pathways such as the mitogen activated protein kinase pathway (MAPK). For instance, decreased activity of TrxR1 alters the phosphorylation status of extracellular signal regulated kinase 1/2 resulting in differential activation of downstream transcription factors such as NF-E2 related factor-2, also known as Nrf2. Therefore, this research illustrates that a decrease in the activity of selenoprotein antioxidants during Se deficiency alters the accumulation of metabolites from the 15-LOX-1 pathway, which in an oxidized environment may result in the downregulation of pro-survival kinase pathways and protective gene responses. Furthermore, these data provide a potential mechanism for the differential expression of HO-1 during Se deficiency and the ensuing physiological disturbances associated with oxidant stress.