Comparison of the Heme Oxygenase/ Carbon Monoxide Pathway and Downstream Cytoprotection between Human and Northern Elephant Seal Vascular Endothelial Cells
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Abstract
Carbon monoxide (CO)- commonly referred to as “the silent killer”- is a gaseous molecule naturally produced in the body at low concentrations during routine heme degradation facilitated by the heme oxygenase (HO-1 and HO-2) enzymes, where CO produced can tightly bind to blood and tissue hemoproteins (e.g., hemoglobin, myoglobin, cytochromes). Interestingly, slightly elevated CO levels in blood and tissues, as well as increased HO activity, is associated with a greater resistance against injuries induced by ischemia/reperfusion, oxidative stress, and inflammation in human and certain terrestrial animal models. Despite experiencing dramatic ischemia/reperfusion and severe hypoxemia during long-duration dives, northern elephant seals ( Mirounga angustirostris) do not exhibit evidence of tissue injuries associated with these events. Notably, this species naturally possesses high CO levels in their blood and skeletal muscles, where values measured are similar to concentrations suggested to elicit cytoprotection in laboratory animals and human clinical trials. However, the role of the HO/CO pathway in relation to northern elephant seal resistance against injuries from ischemia/reperfusion, oxidative stress, and/or inflammation remains uncertain. This study thus compares the HO/CO pathway and downstream cytoprotection in cultured vascular endothelial cells from human and northern elephant seals. Cells of both species were exposed to low doses (0, 5, and 10μM) of free heme-a known cytotoxin and substrate for HO activity- where no difference in cell viability was observed in either species. CO production was also similar between species at 0, 5, and 10μM heme at 25,000 cells per species, though seal cells produced more CO per protein content at 10μM heme (p=0.033). Indeed, fold change for genes in the HO pathway ( HMOX1, NRF2, BVR, and GPx4 ) was significantly higher in seal cells compared to human cells at 10μM heme (p<0.05 for all genes), but not at 5μM heme. Given that elephant seals have the highest mass-specific blood volume reported in mammals, as well as high myoglobin content in their skeletal muscle, these data suggest elephant seal cells possess adaptions in the HO/CO pathway and HO enzyme activity to efficiently regulate higher heme concentrations. Furthermore, 5 and 10μM heme treatments successfully reduced reactive oxygen species (ROS) in both species compared to control, though human cells exhibited a greater reduction in ROS compared to seal cells at 10μM (p=0.036), suggesting that an increase in HO activity- and likely endogenous CO production- better mitigates oxidative stress in human cells. Despite this, cell proliferation positively correlated with exogenous CO treatments in seal cells, which was not observed in human cells. Additionally, low concentrations of exogenous CO (2.5% gas diluted in media) successfully rescued seal cell viability in the presence of inflammation (10ng/mL TNFα), where CO treatments did not affect the viability of human cells in the presence of inflammation. These data suggest elephant seal cells were more sensitive to TNFα than human cells, but elicited a stronger response in the presence of CO. These findings provide insight to the potential adaptive role of CO in elephant seal protection against cytotoxic heme and inflammation, as well as its clinical significance to humans and other terrestrial mammals.NSF Award #1927616This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
