title: Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice.
abstract: To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature's experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole-genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB (-/+) heterozygote mice are treated with lower levels of oxygen (O2), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O2) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O2 delivery to vital organs was significantly higher and blood lactate was lower in EdnrB (-/+) compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower in EdnrB (-/+) mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB (-/+) and wild type. Functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans.
authors.affiliation: Department of Pediatrics, Division of Respiratory Medicine, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Tsering
authors.initials: T
authors.lastname: Stobdan
authors.affiliation: Department of Pediatrics, Division of Respiratory Medicine, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Eilleen
authors.initials: E
authors.lastname: Ao-Ieong
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Daniel
authors.initials: D
authors.lastname: Ortiz
authors.affiliation: Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Roy
authors.initials: R
authors.lastname: Ronen
authors.affiliation: Department of Pediatrics, Division of Respiratory Medicine, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Iain
authors.initials: I
authors.lastname: Hartley
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Zhuohui
authors.initials: Z
authors.lastname: Gan
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
authors.affiliation: Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Vineet
authors.initials: V
authors.lastname: Bafna
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabrales
authors.affiliation: Department of Pediatrics, Division of Respiratory Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093; Rady Children's Hospital, San Diego, CA 92123 ghaddad@ucsd.edu.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Haddad
mesh_terms: D000064:Acclimatization / Q000235:genetics; D000531:Altitude; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000502:physiology; D002302:Cardiac Output / Q000502:physiology; D005002:Ethiopia; D005260:Female; D006321:Heart / Q000502:physiology*; D006579:Heterozygote; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000502:physiology; D009200:Myocardial Contraction; D018994:Myosin Light Chains / Q000502:physiology; D010100:Oxygen / Q000737:chemistry; D011510:Proteolipids / Q000502:physiology; D040641:Quantitative Trait Loci; D044023:Receptor, Endothelin B / Q000235:genetics / Q000502:physiology*; D017422:Sequence Analysis, DNA; D014018:Tissue Distribution
chemical_list: C000588596:EDNRB protein, human; C000602969:EDNRB protein, mouse; C000599129:MYL4 protein, human; D009124:Muscle Proteins; D018994:Myosin Light Chains; C472955:NPPA protein, human; D011510:Proteolipids; D044023:Receptor, Endothelin B; C077258:sarcolipin; D019344:Lactic Acid; D009320:Atrial Natriuretic Factor; D010100:Oxygen
keywords: Endothelin receptor type B; cardiac output; high altitude; hypoxia; lactate