Elephant Seal Endothelial Cells are Resistant to Oxidative Stress

Abstract

Marine mammals experience acute fluctuations in blood flow and oxygen content while diving. In humans and other non-diving species, fluctuations of similar magnitude (e.g., during ischemia/reperfusion events) increase reactive oxygen species generation and oxidative damage. Endothelial cells are particularly susceptible to reperfusion injury, which is associated with vascular pathologies including myocardial infarction and ischemic stroke. Marine mammals, however, are protected against reperfusion injuries, though the precise cellular mechanisms driving this protection remain unclear. To study this phenomenon, we isolated placental arterial endothelial cells from humans and northern elephant seals. Elephant seals are elite divers with extreme hypoxemic tolerance. Seal and human endothelial cells express canonical endothelial cell markers (PECAM-1, VE-cadherin) and respire under basal culture conditions. Seal endothelial cells have lower proton leak and higher respiratory capacity than human cells and respond to pharmacological stimulation of NADPH oxidase. Hypoxia/reoxygenation or treatment with menadione increases oxidant generation in human cells by 5-fold (p=0.027) but not in seal cells (2.5-fold, p=0.18). Similarly, lipid peroxidation increases 2-fold in human (p=0.0002) but not seal (p=0.19) cells treated with organic peroxides, despite lower protein abundance of the phospholipid hydroperoxidases peroxiredoxin 6 (Prdx6) and glutathione peroxidase 4 (Gpx4) in seal cells. These results demonstrate that seal cells possess an intrinsic capacity to cope with oxidants. Moreover, these results highlight the translational potential of identifying the mechanisms driving seals’ natural tolerance to ischemia/reperfusion events.