title: An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells.
abstract: Complex organisms may coordinate molecular responses to hypoxia by specialized avenues of communication across multiple tissues, but these mechanisms are poorly understood. Plasma-based, extracellular microRNAs have been described, yet their regulation and biological functions in hypoxia remain enigmatic. We found a unique pattern of release of the hypoxia-inducible microRNA-210 (miR-210) from hypoxic and reoxygenated cells. This microRNA is also elevated in human plasma in physiologic and pathologic conditions of altered oxygen demand and delivery. Released miR-210 can be delivered to recipient cells, and the suppression of its direct target ISCU and mitochondrial metabolism is primarily evident in hypoxia. To regulate these hypoxia-specific actions, prolyl-hydroxylation of Argonaute 2 acts as a molecular switch that reciprocally modulates miR-210 release and intracellular activity in source cells as well as regulates intracellular activity in recipient cells after miR-210 delivery. Therefore, Argonaute 2-dependent control of released miR-210 represents a unique communication system that integrates the hypoxic response across anatomically distinct cells, preventing unnecessary activity of delivered miR-210 in normoxia while still preparing recipient tissues for incipient hypoxic stress and accelerating adaptation.
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hale
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Changjin
authors.initials: C
authors.lastname: Lee
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Annis
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Cardiology Division, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Pil-Ki
authors.initials: PK
authors.lastname: Min
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Pande
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Creager
authors.affiliation: Department of Emergency Medicine, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA.
authors.forename: Colleen G
authors.initials: CG
authors.lastname: Julian
authors.affiliation: Department of Medicine, and Obstetrics-Gynecology, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA.
authors.forename: Lorna G
authors.initials: LG
authors.lastname: Moore
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: S Alex
authors.initials: SA
authors.lastname: Mitsialis
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Stella
authors.initials: S
authors.lastname: Kourembanas
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA. Electronic address: sychan@partners.org.
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Chan
keywords: Circulating microRNA; Endothelial; Hypoxamir; Hypoxia; Mitochondrial metabolism