UC Merced

While diving, seals are repeatedly exposed to hypoxemia and ischemia/reperfusion. While on land, seals experience sleep apnea and prolonged periods of absolute food and water deprivation. Prolonged fasting, sleep apnea, hypoxemia and ischemia/reperfusion increase oxidant production and oxidative stress in terrestrial mammals. The objectives of this project were to investigate if prolonged fasting and sleep apnea increase oxidative stress in elephant seals and to explore the adaptations seals evolved to cope with increased oxidant production. In the first chapter, we demonstrated that despite activating the renin-angiotensin system and increasing NADPH oxidase expression and activity, prolonged fasting does not increase local or systemic oxidative damage or inflammation. In the second chapter we showed that prolonged fasting increases systemic and local endogenous antioxidant defenses (glutathione and antioxidant enzymes), which likely contribute to the prevention of oxidative damage. The third chapter explored the physiological mechanisms leading to the up-regulation of the antioxidant system during prolonged fasting and demonstrated that systemic increases in the renin-angiotensin system can activate the redox-senstive transcription factor Nrf2 through stimulating the Smad pathway and increasing the expression of NADPH oxidase 4. The fourth chapter shows that rather than inducing local or systemic oxidative damage, repetitive sleep apnea bouts activate protective responses against hypoxia and oxidative stress in elephant seals by increasing the levels of Nrf2 and hypoxia inducible factor 1α (HIF-1α). This is the first work demonstrating the oxidant-mediated activation of hormetic responses against hypoxia and oxidative stress in a large, wild vertebrate. Our findings contribute to expanding our knowledge of the evolution of antioxidant defenses and adaptive responses to oxidative stress. Understanding the mechanisms that allow adapted mammals to avoid oxidative damage has the potential to advance our knowledge of oxidative stress-induced pathologies and to enhance the translative value of biomedical therapies in the long term