Enhanced translation of heme oxygenase-2 preserves human endothelial cell viability during hypoxia.

Abstract

Heme oxygenases (HOs) -1 and -2 catalyze the breakdown of heme to release carbon monoxide, biliverdin, and ferrous iron, which may preserve cell function during oxidative stress. HO-1 levels decrease in endothelial cells exposed to hypoxia, whereas the effect of hypoxia on HO-2 expression is unknown. The current study was carried out to determine if hypoxia alters HO-2 protein levels in human endothelial cells and whether this enzyme plays a role in preserving their viability during hypoxic stress. Human umbilical vein endothelial cells (HUVECs), human aortic endothelial cells (HAECs), and human blood outgrowth endothelial cells were exposed to 21% or 1% O(2) for 48 or 16 h in the presence or absence of tumor necrosis factor-alpha (10 ng/ml) or H(2)O(2) (100 microm). In all three endothelial cell types HO-1 mRNA and protein levels were decreased following hypoxic incubation, whereas HO-2 protein levels were unaltered. In HUVECs HO-2 levels were maintained during hypoxia despite a 57% reduction in steady-state HO-2 mRNA level and a 43% reduction in total protein synthesis. Polysome profiling revealed increased HO-2 transcript association with polysomes during hypoxia consistent with enhanced translation of these transcripts. Importantly, inhibition of HO-2 expression by small interference RNA increased oxidative stress, exacerbated mitochondrial membrane depolarization, and enhanced caspase activation and apoptotic cell death in cells incubated under hypoxic but not normoxic conditions. These data indicate that HO-2 is important in maintaining endothelial viability and may preserve local regulation of vascular tone, thrombosis, and inflammatory responses during reductions in systemic oxygen delivery.

• Authors: Jeff Z He, J J David Ho, Sheena Gingerich, David W Courtman, Philip A Marsden, Michael E Ward
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 13 Pg. 9452-9461 (Mar 26 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20118244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Necrosis Factor-alpha
• Hydrogen Peroxide
• Heme Oxygenase (Decyclizing)
• heme oxygenase-2

Topics

• Cell Survival
• Cells, Cultured
• Endothelial Cells (enzymology, pathology)
• Endothelium, Vascular (cytology, pathology)
• Heme Oxygenase (Decyclizing) (metabolism)
• Humans
• Hydrogen Peroxide (chemistry)
• Hypoxia
• Inflammation
• Membrane Potentials
• Mitochondrial Membranes (metabolism)
• Oxidative Stress
• RNA Interference
• Time Factors
• Tumor Necrosis Factor-alpha (metabolism)