title: Hypoxia sensing throughβ-adrenergic receptors.
abstract: Life-sustaining responses to low oxygen, or hypoxia, depend on signal transduction by HIFs, but the underlying mechanisms by which cells sense hypoxia are not completely understood. Based on prior studies suggesting a link between the β-adrenergic receptor (β-AR) and hypoxia responses, we hypothesized that the β-AR mediates hypoxia sensing and is necessary for HIF-1α accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo. Likewise, beta blocker treatment of primary human endothelial cells in vitro decreased hypoxia-mediated HIF-1α accumulation and binding to target genes and the downstream hypoxia-inducible gene expression. In mechanistic studies, cAMP-activated PKA and/or GPCR kinases (GRK), which both participate in β-AR signal transduction, were investigated. Direct activation of cAMP/PKA pathways did not induce HIF-1α accumulation, and inhibition of PKA did not blunt HIF-1α induction by hypoxia. In contrast, pharmacological inhibition of GRK, or expression of a GRK phosphorylation-deficient β-AR mutant in cells, blocked hypoxia-mediated HIF-1α accumulation. Mass spectrometry-based quantitative analyses revealed a hypoxia-mediated β-AR phosphorylation barcode that was different from the classical agonist phosphorylation barcode. These findings indicate that the β-AR is fundamental to the molecular and physiological responses to hypoxia.
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Hoi I
authors.initials: HI
authors.lastname: Cheong
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Kewal
authors.initials: K
authors.lastname: Asosingh
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Olivia R
authors.initials: OR
authors.lastname: Stephens
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Queisser
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Weiling
authors.initials: W
authors.lastname: Xu
authors.affiliation: Proteomics and Metabolomics Laboratory, Lerner Research Institute.
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.affiliation: Department of Quantitative Health Sciences.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.affiliation: Pathology & Laboratory Medicine Institute.
authors.forename: Josephine Kam Tai
authors.initials: JKT
authors.lastname: Dermawan
authors.affiliation: Department of Cancer Biology, Lerner Research Institute.
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, and.
authors.forename: Sathyamangla V
authors.initials: SV
authors.lastname: Naga Prasad
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.|Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum