Adaptive responses and apoptosis in endothelial cells exposed to carbon monoxide

Abstract

Prior studies have shown that exposure to carbon monoxide (CO) will elevate the steady-state concentration of nitric oxide ( ⅐ NO) in several cell types and body organs and that some toxic effects of CO are directed toward endothelial cells. Studies reported in this paper were conducted with bovine pulmonary artery endothelial cells exposed to 10 to 100 ppm CO to achieve concentrations between 11 and 110 nM in air-saturated buffer. Exposure to 11 nM CO increased synthesis of manganous superoxide dismutase and conferred resistance against the lethal effects of 110 nM CO. At concentrations of 88 nM CO or more, exposures for 1 h or longer caused cell death that became apparent 18 h after the exposure ceased. Caspase-1 was activated in response to CO, and cell death was inhibited by a caspase-1 inhibitor. Alteration of proteolytic pathways by CO was indicated by the presence of ubiquitincontaining intracellular inclusion bodies. Morphological changes and caspase activation indicated that cell death was an apoptotic process. Cells exposed to 110 nM CO had higher concentrations of manganous superoxide dismutase and heme oxygenase-1 but no changes in glutathione peroxidase, glucose-6-phosphate dehydrogenase, thiols, or catalase. Elevated levels of antioxidant enzymes and apoptosis were inhibited by the nitric oxide synthase inhibitor, S-isopropylisothiourea, and the peroxynitrite scavenger, selenomethionine. These results show that biochemical effects of CO occur at environmentally relevant concentrations, that apoptotic cell death follows exposure to relatively high concentrations of CO, and that these actions of CO are mediated by nitric oxide. C arbon monoxide (CO) is a ubiquitous environmental pollutant. The National Ambient Air Quality Standards in the United States for CO have been set at 35 ppm for a 1-h average exposure, and 9 ppm for an 8-h average exposure. Concentrations of CO found in urban environments have been correlated with hospital admissions, mortality, and morbidity caused by cardiovascular and pulmonary diseases (1-8). Average CO concentrations have been found to be 1-9 ppm, but there are many occupational settings where exposures exceed these levels (9-17). The carboxyhemoglobin values associated with levels of CO typically found in the environment are so low that a direct hypoxic stress is doubtful and compensatory responses are sufficient to maintain tissue oxygenation (18-21). Therefore, the pathophysiological basis for toxic effects of low concentrations of CO is not clear.The goal of the current investigation was to evaluate the mechanism for cell death and manifestations of oxidative stress in cultured endothelial cells exposed to CO. Studies in humans have suggested that CO exposures will cause vascular and perivascular abnormalities (22-25); these suggestions increase interest regarding the effects of CO on endothelial cells. Our previous work with experimental animals has shown that CO has a number of effects on the vasculature. Nitrotyrosine is a major product when peroxynitrite reacts w...

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