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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091767-03
Application #
8015226
Study Section
Special Emphasis Panel (ZRG1-CVS-A (50))
Program Officer
Wong, Renee P
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
3
Fiscal Year
2011
Total Cost
$412,637
Indirect Cost
Name
University of California Merced
Department
Type
Schools of Earth Sciences/Natur
DUNS #
113645084
City
Merced
State
CA
Country
United States
Zip Code
95343
Rodriguez, Ruben; Minas, Jacqueline N; Vazquez-Medina, Jose Pablo et al. (2018) Chronic AT1 blockade improves glucose homeostasis in obese OLETF rats. J Endocrinol 237:271-284
Thorwald, Max; Rodriguez, Ruben; Lee, Andrew et al. (2018) Angiotensin receptor blockade improves cardiac mitochondrial activity in response to an acute glucose load in obese insulin resistant rats. Redox Biol 14:371-378
Martinez, Bridget; Scheibner, Michael; Soñanez-Organis, José G et al. (2017) Increased sensitivity of thyroid hormone-mediated signaling despite prolonged fasting. Gen Comp Endocrinol 252:36-47
Vazquez-Anaya, Guillermo; Martinez, Bridget; Soñanez-Organis, José G et al. (2017) Exogenous thyroxine improves glucose intolerance in insulin-resistant rats. J Endocrinol 232:501-511
Minas, Jacqueline N; Thorwald, Max A; Conte, Debra et al. (2015) Angiotensin and mineralocorticoid receptor antagonism attenuates cardiac oxidative stress in angiotensin II-infused rats. Clin Exp Pharmacol Physiol 42:1178-88
Khudyakov, Jane I; Preeyanon, Likit; Champagne, Cory D et al. (2015) Transcriptome analysis of northern elephant seal (Mirounga angustirostris) muscle tissue provides a novel molecular resource and physiological insights. BMC Genomics 16:64
Suzuki, Miwa; Lee, Andrew Y; Vázquez-Medina, José Pablo et al. (2015) Plasma FGF21 concentrations, adipose fibroblast growth factor receptor-1 and ?-klotho expression decrease with fasting in northern elephant seals. Gen Comp Endocrinol 216:86-9
Khudyakov, Jane I; Champagne, Cory D; Preeyanon, Likit et al. (2015) Muscle transcriptome response to ACTH administration in a free-ranging marine mammal. Physiol Genomics 47:318-30
Sharick, J T; Vazquez-Medina, J P; Ortiz, R M et al. (2015) Oxidative stress is a potential cost of breeding in male and female northern elephant seals. Funct Ecol 29:367-376
Tift, Michael S; Ponganis, Paul J; Crocker, Daniel E (2014) Elevated carboxyhemoglobin in a marine mammal, the northern elephant seal. J Exp Biol 217:1752-7

Showing the most recent 10 out of 29 publications