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2457 Erythrocyte Intracellular Adenosine Regulates Oxygen Release Combating Tissue Hypoxia, Inflammation and Fibrosis

Program: Oral and Poster Abstracts
Session: 101. Red Cells and Erythropoiesis, Excluding Iron: Poster II
Hematology Disease Topics & Pathways:
Fundamental Science, Research
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Changhan Chen1*, Tingting Xie1*, Yujin Zhang1*, Yiyan Wang1*, Fang Yu1*, Lizhen Lin1*, Weiru Zhang1*, Benjamin C. Brown2*, Xin Zhang1*, Rodney E. Kellems3*, Angelo D'Alessandro, PhD4 and Yang Xia, MD, PhD1*

1Xiangya Hospital, Central South University, Changsha, China
2Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Denver
3The University of Texas McGovern Medical School at Houston, Houston
4Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO

Hypoxia is considered a common cause of myriad diseases and drives tissue damage and progression. Erythrocytes are vital under hypoxia since they can sense and act rapidly to hypoxia by promoting metabolomic reprogramming and oxygen (O2) release. Adenosine monophosphate deaminase 3 (AMPD3) is highly enriched in erythrocytes and plays an important role in maintaining erythrocyte intracellular purine homeostasis. However, how it senses and regulates oxygen release remains poorly understood. Here we report that genetic ablation of AMPD3 led to more O2 release from erythrocytes, resulting in less tissue hypoxia, damage, inflammation and fibrosis in two independent pathological hypoxia models including Angiotensin II infusion and unilateral ureteric obstruction (UUO) models. Metabolically, untargeted high-throughput metabolomic profiling in erythrocytes revealed that nucleotides including AMP, ADP and ATP levels were significantly increased in WT mice and further elevated in Ampd3-/- mice. Isotopically adenosine flux experiment demonstrated that adenosine was rapidly and largely converted to AMP. At molecular level, we further demonstrated that hypoxia-induced AMPD3 activity as a compensatory mechanism led to accumulation of AMP, subsequently inducing AMP kinase (AMPK)-dependent metabolic reprogramming by inducing bisphosphoglycerate mutase (BPGM), which shifts glycolysis toward erythroid unique Rapoport-Leubering Shunt (RSL) to promote 2,3-BPG production, O2 delivery and anti-ROS capacity to mitigate tissue hypoxia, dysfunction, inflammation and fibrosis. At cellular level, we revealed that hypoxia directly inhibited AMPD3, leading to activation of AMPK by lowering ROS in both cultured primary human and murine erythrocytes. Finally, we conducted human translational studies demonstrating that the production of 2,3-BPG, BPGM activity, p-AMPK level, and P50 were increased, while AMPD3 activity was decreased in patients with chronic kidney disease (a common pathological condition) compared with normal controls. Altogether, eAMPD3 is a previously unrecognized master intracellular purinergic component sensing hypoxia and promoting adaptative metabolic reprogramming to mitigate tissue hypoxia, insufficient energy, tissue damage and fibrosis by enhancing O2 delivery and antioxidative stress capacity in a positive feedforward manner.

Disclosures: D'Alessandro: Hemanext Inc: Consultancy; Macopharma: Consultancy; Omix Technologies Inc: Current equity holder in private company.

*signifies non-member of ASH