Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming.

Autor: Qiang Q; Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.; Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas, United States of America., Manalo JM; Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas, United States of America.; University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, Texas, United States of America., Sun H; Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China., Zhang Y; Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas, United States of America., Song A; Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas, United States of America., Wen AQ; Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas, United States of America.; University of California at San Diego, La Jolla, California, United States of America., Wen YE; Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas, United States of America.; University of Texas Southwestern Medical School, Dallas, Texas, United States of America., Chen C; Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.; Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas, United States of America., Liu H; Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas, United States of America.; Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China., Cui Y; Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas, United States of America., Nemkov T; Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, United States of America., Reisz JA; Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, United States of America., Edwards Iii G; University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, Texas, United States of America.; Department of Neurology, The University of Texas McGovern Medical School, Houston, Texas, United States of America., Perreira FA; Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, United States of America., Kellems RE; Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas, United States of America.; University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, Texas, United States of America., Soto C; Department of Neurology, The University of Texas McGovern Medical School, Houston, Texas, United States of America., D'Alessandro A; Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, United States of America., Xia Y; Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas, United States of America.; University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, Texas, United States of America.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2021 Jun 17; Vol. 19 (6), pp. e3001239. Date of Electronic Publication: 2021 Jun 17 (Print Publication: 2021).
DOI: 10.1371/journal.pbio.3001239
Abstrakt: Hypoxia drives aging and promotes age-related cognition and hearing functional decline. Despite the role of erythrocytes in oxygen (O2) transport, their role in the onset of aging and age-related cognitive decline and hearing loss (HL) remains undetermined. Recent studies revealed that signaling through the erythrocyte adenosine A2B receptor (ADORA2B) promotes O2 release to counteract hypoxia at high altitude. However, nothing is known about a role for erythrocyte ADORA2B in age-related functional decline. Here, we report that loss of murine erythrocyte-specific ADORA2B (eAdora2b-/-) accelerates early onset of age-related impairments in spatial learning, memory, and hearing ability. eAdora2b-/- mice display the early aging-like cellular and molecular features including the proliferation and activation of microglia and macrophages, elevation of pro-inflammatory cytokines, and attenuation of hypoxia-induced glycolytic gene expression to counteract hypoxia in the hippocampus (HIP), cortex, or cochlea. Hypoxia sufficiently accelerates early onset of cognitive and cochlear functional decline and inflammatory response in eAdora2b-/- mice. Mechanistically, erythrocyte ADORA2B-mediated activation of AMP-activated protein kinase (AMPK) and bisphosphoglycerate mutase (BPGM) promotes hypoxic and metabolic reprogramming to enhance production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite triggering O2 delivery. Significantly, this finding led us to further discover that murine erythroblast ADORA2B and BPGM mRNA levels and erythrocyte BPGM activity are reduced during normal aging. Overall, we determined that erythrocyte ADORA2B-BPGM axis is a key component for anti-aging and anti-age-related functional decline.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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