Abstract 16038: Heterozygous Endothelin Receptor Type B Knockout Confers Cardiac Resistance to Extreme Hypoxia in Mice
Rationale: To better understand human adaptation to hypoxia, we took advantage of one of the nature’s experiments at high altitude (HA) and studied Ethiopians, a human population that is well adapted to HA hypoxia. Using whole genome sequencing, we identified EDNRB, endothelin receptor type B, as a candidate gene involved in HA adaptation.
Objective: We hypothesize that EDNRB plays a critical role in hypoxia and therefore in HA adaptation through regulating cardiac function.
Methods and Results: We generated EdnrB knockout mice and found that the EdnrB-/+ mice were phenotypically normal. However, when treated with lower levels of oxygen (O2), EdnrB-/+ mice tolerated various levels of hypoxia, sustaining ejection fraction, cardiac contractility and cardiac output to even 5% O2. Blood lactate levels remained low and O2 delivery to vital organs was significantly higher in EdnrB-/+. Tissues sensitive to hypoxia, such as brain, heart and kidney, were less hypoxic indicating better peripheral perfusion.
Conclusion: These data indicate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Our findings in EdnrB-/+ mice provide strong evidence that 1) EDNRB plays a key role in the adaptation to HA whereby a lower activation of EDNRB leads to a better cardiac performance under hypoxic conditions and 2) HA adaptation studies can be pertinent to understanding responses to acute hypoxia at sea level.
Author Disclosures: T. Stobdan: None. D. Zhou: None. E. Ao-Ieong: None. D. Ortiz: None. R. Ronen: None. V. Bafna: None. P. Cabrales: Research Grant; Significant; P01-HL110900, R56HL123015, and R01-HL52684. G.G. Haddad: Research Grant; Significant; PO1 HL098053.
- © 2015 by American Heart Association, Inc.