Hypoxia exposure blunts angiogenic signaling and upregulates the antioxidant system in endothelial cells derived from elephant seals.

BACKGROUND: Elephant seals exhibit extreme hypoxemic tolerance derived from repetitive hypoxia/reoxygenation episodes they experience during diving bouts. Real-time assessment of the molecular changes underlying protection against hypoxic injury in seals remains restricted by their at-sea inaccessibility. Hence, we developed a proliferative arterial endothelial cell culture model from elephant seals and used RNA-seq, functional assays, and confocal microscopy to assess the molecular response to prolonged hypoxia. RESULTS: Seal and human endothelial cells exposed to 1% O2 for up to 6 h respond differently to acute and prolonged hypoxia. Seal cells decouple stabilization of the hypoxia-sensitive transcriptional regulator HIF-1α from angiogenic signaling. Rapid upregulation of genes involved in glutathione (GSH) metabolism supports the maintenance of GSH pools, and intracellular succinate increases in seal but not human cells. High maximal and spare respiratory capacity in seal cells after hypoxia exposure occurs in concert with increasing mitochondrial branch length and independent from major changes in extracellular acidification rate, suggesting that seal cells recover oxidative metabolism without significant glycolytic dependency after hypoxia exposure. CONCLUSIONS: We found that the glutathione antioxidant system is upregulated in seal endothelial cells during hypoxia, while this system remains static in comparable human cells. Furthermore, we found that in contrast to human cells, hypoxia exposure rapidly activates HIF-1 in seal cells, but this response is decoupled from the canonical angiogenesis pathway. These results highlight the unique mechanisms that confer extraordinary tolerance to limited oxygen availability in a champion diving mammal.

Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism.

No longer viewed as a metabolic waste product and cause of muscle fatigue, a contemporary view incorporates the roles of lactate in metabolism, sensing and signaling in normal as well as pathophysiological conditions. Lactate exists in millimolar concentrations in muscle, blood, and other tissues and can rise more than an order of magnitude as the result of increased production and clearance limitations. Lactate exerts its powerful driver-like influence by mass action, redox change, allosteric binding, and other mechanisms described in this article. Depending on the condition, such as during rest and exercise, following carbohydrate nutrition, injury, or pathology, lactate can serve as a myokine or exerkine with autocrine-, paracrine-, and endocrine-like functions that have important basic and translational implications. For instance, lactate signaling is: involved in reproductive biology, fueling the heart, muscle adaptation, and brain executive function, growth and development, and a treatment for inflammatory conditions. Lactate also works with many other mechanisms and factors in controlling cardiac output and pulmonary ventilation during exercise. Ironically, lactate can be disruptive of normal processes such as insulin secretion when insertion of lactate transporters into pancreatic ß-cell membranes is not suppressed, and in carcinogenesis when factors that suppress carcinogenesis are inhibited, whereas factors that promote carcinogenesis are upregulated. Lactate signaling is important in areas of intermediary metabolism, redox biology, mitochondrial biogenesis, neurobiology, gut physiology, appetite regulation, nutrition, and overall health and vigor. The various roles of lactate as a myokine and exerkine are reviewed.NEW & NOTEWORTHY Lactate sensing and signaling is a relatively new and rapidly changing field. As a physiological signal lactate works both independently and in concert with other signals. Lactate operates via covalent binding and canonical signaling, redox change, and lactylation of DNA. Lactate can also serve as an element of feedback loops in cardiopulmonary regulation. From conception through aging lactate is not the only a myokine or exerkine, but it certainly deserves consideration as a physiological signal.