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Circulation. 2016 Aug 2;134(5):405-21. doi: 10.1161/CIRCULATIONAHA.116.021311.

Beneficial Role of Erythrocyte Adenosine A2B Receptor-Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia.

Author information

1
From the Department of Biochemistry and Molecular Biology (H.L., Y.Z., H.W., A.S., K.S., J.L., N.-Y.C., A.H., Y.E.W., T.T.W., F.L., R.E.K., H.K.-Q., M.R.B., Y.X.), Graduate School of Biomedical Sciences (H.L., K.S., R.E.K., M.R.B., Y.X.), and Department of Pathology (B.Z.), University of Texas Health Science Center at Houston; Departments of Otolaryngology (H.L., H.S.) and Nephrology (Y.X.), Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora (A.D., T.N., K.C.H.); Medicity Research Laboratory, University of Turku, Turku, Finland (G.G.Y.); Altitude Research Center, Department of Emergency Medicine (A.W.S., S.J.-V.H., C.G.J., R.C.R.), and Organ Protection Program, Department of Anesthesiology (H.K.E.), University of Colorado School of Medicine, Aurora; and Department of Human Physiology, University of Oregon, Eugene (A.TL.).
2
From the Department of Biochemistry and Molecular Biology (H.L., Y.Z., H.W., A.S., K.S., J.L., N.-Y.C., A.H., Y.E.W., T.T.W., F.L., R.E.K., H.K.-Q., M.R.B., Y.X.), Graduate School of Biomedical Sciences (H.L., K.S., R.E.K., M.R.B., Y.X.), and Department of Pathology (B.Z.), University of Texas Health Science Center at Houston; Departments of Otolaryngology (H.L., H.S.) and Nephrology (Y.X.), Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora (A.D., T.N., K.C.H.); Medicity Research Laboratory, University of Turku, Turku, Finland (G.G.Y.); Altitude Research Center, Department of Emergency Medicine (A.W.S., S.J.-V.H., C.G.J., R.C.R.), and Organ Protection Program, Department of Anesthesiology (H.K.E.), University of Colorado School of Medicine, Aurora; and Department of Human Physiology, University of Oregon, Eugene (A.TL.). yang.xia@uth.tmc.edu.

Abstract

BACKGROUND:

High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia.

METHODS:

Using high-throughput, unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O2 binding affinity, was significantly induced in 21 healthy humans within 2 hours of arrival at 5260 m and further increased after 16 days at 5260 m.

RESULTS:

This finding led us to discover that plasma adenosine concentrations and soluble CD73 activity rapidly increased at high altitude and were associated with elevated erythrocyte 2,3-BPG levels and O2 releasing capacity. Mouse genetic studies demonstrated that elevated CD73 contributed to hypoxia-induced adenosine accumulation and that elevated adenosine-mediated erythrocyte A2B adenosine receptor activation was beneficial by inducing 2,3-BPG production and triggering O2 release to prevent multiple tissue hypoxia, inflammation, and pulmonary vascular leakage. Mechanistically, we demonstrated that erythrocyte AMP-activated protein kinase was activated in humans at high altitude and that AMP-activated protein kinase is a key protein functioning downstream of the A2B adenosine receptor, phosphorylating and activating BPG mutase and thus inducing 2,3-BPG production and O2 release from erythrocytes. Significantly, preclinical studies demonstrated that activation of AMP-activated protein kinase enhanced BPG mutase activation, 2,3-BPG production, and O2 release capacity in CD73-deficient mice, in erythrocyte-specific A2B adenosine receptor knockouts, and in wild-type mice and in turn reduced tissue hypoxia and inflammation.

CONCLUSIONS:

Together, human and mouse studies reveal novel mechanisms of hypoxia adaptation and potential therapeutic approaches for counteracting hypoxia-induced tissue damage.

KEYWORDS:

AMP-activated protein kinases; adenosine; altitude; hypoxia, brain; oxygen; signal transduction

PMID:
27482003
PMCID:
PMC6168195
DOI:
10.1161/CIRCULATIONAHA.116.021311
[Indexed for MEDLINE]
Free PMC Article

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