Mechanisms of Oxidative Stress and Inflammation during Prolonged Fasting and Slee

Summary

Principal Investigator: Rudy Ortiz
Affiliation: University of California
Country: USA
Abstract: Northern elephant seals have evolved robust physiological mechanisms that have allowed them to adapt to a number of extreme environmental conditions that in humans or other mammals would evoke a number of cardiovascular and respiratory complications. For example, all elephant seals experience protracted periods of absolute food and water deprivation for up to 3 months without exhibiting any indices of dehydration or electrolyte imbalances. At 1 month of age, pups are abruptly weaned and commence a 2- 3 month long fast, all-the-while continuing to develop organ systems required for diving that will ensue following their postweaning fast. While at sea elephant seals routinely dive to depths in excess of 500 m remaining submerged for 40-60 mins followed by return to the surface for gas exchange for only 2-3 mins before the next dive. In addition, elephant seals exhibit chronic (80% of time) bouts of sleep apnea (11 min) that induce arterial P02 of 40 mmHg within 3 min. Independently, any of these behaviors could potentially evoke a number of cardiovascular and respiratory complications;however elephant seals have evolved mechanisms to counter the deleterious effects of these behaviors collectively, which is unparalleled amongst mammals. Because this initiative will support studies to begin to elucidate the mechanisms evolved in mammals uniquely adapted to extreme environmental conditions that evoke life-threatening cardiovascular and respiratory responses in humans, the elephant seal provides an ideal model to fulfill these requirements. This proposal will elucidate in elephant seals the cellular and systemic mechanisms of oxidative stress and inflammation commonly associated with prolonged food and water deprivation and sleep apnea. Our specific aims are: 1) to elucidate the contribution of elevated angiotensin II to the cellular mechanisms of oxidative stress and inflammation by quantifying circulating and cellular markers of oxidative stress and inflammation during prolonged fasting in elephant seals, 2) to elucidate the contribution of increased cortisol to the cellular mechanisms of oxidative stress and inflammation by quantifying circulating and cellular markers of oxidative stress and inflammation during prolonged fasting in elephant seals, and 3) to elucidate the cellular antioxidant and anti-inflammatory mechanisms induced during prolonged sleep apnea-induced hypoxia in naturally adapted elephant seals. Because the renin- angiotensin system (RAS) and cortisol are known to change with fasting in this species, we will focus on the contribution of RAS and glucocorticoids to mediating oxidative stress and inflammation during fasting and sleep apnea. Completion of these aims will provide novel information on the adapted mechanisms evolved by elephant seals to minimize or alleviate the consequences of oxidative stress and inflammation commonly associated with protracted food deprivation and sleep apnea in humans in an effort to identify novel therapeutic targets. PUBLIC HEALTH RELEVANCE: Elephant seals experience prolonged periods of food and water deprivation in addition to chronic sleep apnea-induced hypoxia, both of which can rapidly evoke cardiovascular and respiratory complications in humans. However, these seals must have evolved uniquely robust physiological and cellular mechanisms to counter the potentially detrimental consequences commonly associated with these behaviors. Elucidation of these mechanisms in seals may reveal novel therapeutic targets to help alleviate these consequences in humans. The proposed studies provide the initial steps towards developing the Northern elephant seal as a viable biomedical model to study the natural adaptations evolved to counter oxidative stress and inflammatory events commonly induced by prolonged food deprivation and, sleep- and diving-associated hypoxia.
Funding Period: 2009-02-01 - 2014-01-31
more information: NIH RePORT

Top Publications

  1. pmc Elevated carboxyhemoglobin in a marine mammal, the northern elephant seal
    Michael S Tift
    Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093 0204, USA Department of Biology, Sonoma State University, Rohnert Park, CA 94928, USA
    J Exp Biol 217:1752-7. 2014
  2. pmc Elucidating nature's solutions to heart, lung, and blood diseases and sleep disorders
    Hannah V Carey
    Department of Comparative Biosciences, University of Wisconsin Madison, 2015 Linden Drive, Madison, WI 53706, USA
    Circ Res 110:915-21. 2012
  3. pmc Angiotensin receptor blockade recovers hepatic UCP2 expression and aconitase and SDH activities and ameliorates hepatic oxidative damage in insulin resistant rats
    Priscilla Montez
    Department of Molecular and Cellular Biology, University of California, Merced, CA 95343, USA
    Endocrinology 153:5746-59. 2012
  4. pmc Coping with physiological oxidative stress: a review of antioxidant strategies in seals
    José Pablo Vázquez-Medina
    School of Natural Sciences, University of California Merced, 5200 N Lake Road, Merced, CA 95343, USA
    J Comp Physiol B 182:741-50. 2012
  5. pmc Cellular mechanisms regulating fuel metabolism in mammals: role of adipose tissue and lipids during prolonged food deprivation
    Jose Abraham Viscarra
    Department of Molecular and Cellular Biology, University of California, Merced, 5200 N Lake Rd, Merced, CA 95343, USA
    Metabolism 62:889-97. 2013
  6. pmc Activation of systemic, but not local, renin-angiotensin system is associated with upregulation of TNF-α during prolonged fasting in northern elephant seal pups
    Miwa Suzuki
    Department of Molecular and Cellular Biology, University of California Merced, Merced, CA 95343, USA
    J Exp Biol 216:3215-21. 2013
  7. pmc Prolonged fasting activates hypoxia inducible factors-1α, -2α and -3α in a tissue-specific manner in northern elephant seal pups
    José G Soñanez-Organis
    School of Natural Sciences, University of California, Merced, 5200 N Lake Road, Merced, CA 95343, USA
    Gene 526:155-63. 2013
  8. pmc Angiotensin receptor-mediated oxidative stress is associated with impaired cardiac redox signaling and mitochondrial function in insulin-resistant rats
    José Pablo Vázquez-Medina
    Department of Molecular and Cellular Biology, School of Natural Sciences, University of California Merced, Merced, California
    Am J Physiol Heart Circ Physiol 305:H599-607. 2013
  9. pmc Decreased expression of adipose CD36 and FATP1 are associated with increased plasma non-esterified fatty acids during prolonged fasting in northern elephant seal pups (Mirounga angustirostris)
    Jose Abraham Viscarra
    School of Natural Sciences, University of California Merced, Merced, CA 95343, USA
    J Exp Biol 215:2455-64. 2012
  10. pmc Prolonged fasting increases purine recycling in post-weaned northern elephant seals
    José Guadalupe Soñanez-Organis
    School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, CA 95343, USA
    J Exp Biol 215:1448-55. 2012

Scientific Experts

  • Jose A Viscarra
  • Segal M Boaz
  • José Pablo Vázquez-Medina
  • Rudy M Ortiz
  • Daniel E Crocker
  • Tania Zenteno-Savin
  • José G Soñanez-Organis
  • Ruben Rodriguez
  • Michael S Tift
  • Akira Nishiyama
  • Daisuke Nakano
  • José Guadalupe Soñanez-Organis
  • Henry Jay Forman
  • Miwa Suzuki
  • Max A Thorwald
  • Janos Peti-Peterdi
  • Lisa Lam
  • Priscilla Montez
  • Hannah V Carey
  • Paul J Ponganis
  • Irina Popovich
  • José P Vázquez-Medina
  • Robert Elsner
  • Jacqueline N Minas
  • Lin Yan
  • Sandra L Martin
  • Renee P Wong
  • David A Lathrop
  • Jason Podrabsky
  • Andres Aguilar
  • Barbara A Horwitz
  • Jay F Storz
  • Shannon M Bailey
  • Jennifer M Burns

Detail Information

Publications20

  1. pmc Elevated carboxyhemoglobin in a marine mammal, the northern elephant seal
    Michael S Tift
    Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093 0204, USA Department of Biology, Sonoma State University, Rohnert Park, CA 94928, USA
    J Exp Biol 217:1752-7. 2014
    ....
  2. pmc Elucidating nature's solutions to heart, lung, and blood diseases and sleep disorders
    Hannah V Carey
    Department of Comparative Biosciences, University of Wisconsin Madison, 2015 Linden Drive, Madison, WI 53706, USA
    Circ Res 110:915-21. 2012
    ....
  3. pmc Angiotensin receptor blockade recovers hepatic UCP2 expression and aconitase and SDH activities and ameliorates hepatic oxidative damage in insulin resistant rats
    Priscilla Montez
    Department of Molecular and Cellular Biology, University of California, Merced, CA 95343, USA
    Endocrinology 153:5746-59. 2012
    ..Thus, in addition to promoting obesity-related hypertension, AT1 activation may also impair lipid metabolism and antioxidant capacity, resulting in steatosis via decreased UCP2 and tricarboxylic acid cycle activity...
  4. pmc Coping with physiological oxidative stress: a review of antioxidant strategies in seals
    José Pablo Vázquez-Medina
    School of Natural Sciences, University of California Merced, 5200 N Lake Road, Merced, CA 95343, USA
    J Comp Physiol B 182:741-50. 2012
    ....
  5. pmc Cellular mechanisms regulating fuel metabolism in mammals: role of adipose tissue and lipids during prolonged food deprivation
    Jose Abraham Viscarra
    Department of Molecular and Cellular Biology, University of California, Merced, 5200 N Lake Rd, Merced, CA 95343, USA
    Metabolism 62:889-97. 2013
    ....
  6. pmc Activation of systemic, but not local, renin-angiotensin system is associated with upregulation of TNF-α during prolonged fasting in northern elephant seal pups
    Miwa Suzuki
    Department of Molecular and Cellular Biology, University of California Merced, Merced, CA 95343, USA
    J Exp Biol 216:3215-21. 2013
    ..These data enhance our understanding of the adaptive mechanisms evolved by elephant seals to tolerate potentially detrimental conditions. ..
  7. pmc Prolonged fasting activates hypoxia inducible factors-1α, -2α and -3α in a tissue-specific manner in northern elephant seal pups
    José G Soñanez-Organis
    School of Natural Sciences, University of California, Merced, 5200 N Lake Road, Merced, CA 95343, USA
    Gene 526:155-63. 2013
    ....
  8. pmc Angiotensin receptor-mediated oxidative stress is associated with impaired cardiac redox signaling and mitochondrial function in insulin-resistant rats
    José Pablo Vázquez-Medina
    Department of Molecular and Cellular Biology, School of Natural Sciences, University of California Merced, Merced, California
    Am J Physiol Heart Circ Physiol 305:H599-607. 2013
    ....
  9. pmc Decreased expression of adipose CD36 and FATP1 are associated with increased plasma non-esterified fatty acids during prolonged fasting in northern elephant seal pups (Mirounga angustirostris)
    Jose Abraham Viscarra
    School of Natural Sciences, University of California Merced, Merced, CA 95343, USA
    J Exp Biol 215:2455-64. 2012
    ..Delineation of the mechanisms responsible for this shift in regulation during fasting can contribute to a more thorough understanding of the changes in lipid metabolism associated with dyslipidemia and insulin resistance in mammals...
  10. pmc Prolonged fasting increases purine recycling in post-weaned northern elephant seals
    José Guadalupe Soñanez-Organis
    School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, CA 95343, USA
    J Exp Biol 215:1448-55. 2012
    ....
  11. pmc Angiotensin receptor blockade increases pancreatic insulin secretion and decreases glucose intolerance during glucose supplementation in a model of metabolic syndrome
    Ruben Rodriguez
    School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, California 95343, USA
    Endocrinology 153:1684-95. 2012
    ....
  12. pmc Apnea stimulates the adaptive response to oxidative stress in elephant seal pups
    José Pablo Vázquez-Medina
    School of Natural Sciences, University of California, Merced, Merced, CA 95343, USA
    J Exp Biol 214:4193-200. 2011
    ....
  13. pmc Water-soluble vitamin homeostasis in fasting northern elephant seals (Mirounga angustirostris) measured by metabolomics analysis and standard methods
    Segal M Boaz
    Sonoma State University, Department of Biology, 1801 E Cotati Ave, Rohnert Park, CA 94928, USA
    Comp Biochem Physiol A Mol Integr Physiol 161:114-21. 2012
    ..Modifications to the analysis platforms and compound detection algorithms used in this study may be required for improving water-soluble vitamin detection in this and other novel wildlife systems...
  14. pmc Antioxidant capacity develops with maturation in the deep-diving hooded seal
    José Pablo Vázquez-Medina
    School of Natural Sciences, University of California Merced, 5200 N Lake Road, Merced, CA 95343, USA
    J Exp Biol 214:2903-10. 2011
    ....
  15. pmc Prolonged fasting increases glutathione biosynthesis in postweaned northern elephant seals
    José Pablo Vázquez-Medina
    School of Natural Sciences, University of California Merced, Merced, CA 95343, USA
    J Exp Biol 214:1294-9. 2011
    ..Results indicate that GSH biosynthesis increases with fasting and that GSH contributes to counteracting hydroperoxide production, preventing oxidative damage in fasting seals...
  16. pmc 5'AMP-activated protein kinase activity is increased in adipose tissue of northern elephant seal pups during prolonged fasting-induced insulin resistance
    Jose A Viscarra
    School of Natural Sciences, University of California, Merced, California 95348, USA
    J Endocrinol 209:317-25. 2011
    ..The association between increased AMPK activity and Glut4 expression suggests that AMPK plays a greater role in regulating glucose metabolism in mammals adapted to prolonged fasting than in non-fasting mammals...
  17. pmc Glut4 is upregulated despite decreased insulin signaling during prolonged fasting in northern elephant seal pups
    Jose A Viscarra
    University of California, Merced, 95343, USA
    Am J Physiol Regul Integr Comp Physiol 300:R150-4. 2011
    ..The reduction of plasma glucose independent of insulin may make these animals an ideal model for the study of insulin resistance...
  18. pmc Prolonged fasting does not increase oxidative damage or inflammation in postweaned northern elephant seal pups
    José Pablo Vázquez-Medina
    School of Natural Sciences, University of California, Merced, CA 95343, USA
    J Exp Biol 213:2524-30. 2010
    ..The present study highlights the importance of antioxidant capacity in mammals during chronic periods of stress to help avoid deleterious systemic consequences...