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Hypoxia sensing through ?-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 ?-adrenergic receptor (?-AR) and hypoxia responses, we hypothesized that the ?-AR mediates hypoxia sensing and is necessary for HIF-1? accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1? accumulation, erythropoietin production, and erythropoiesis in vivo. Likewise, beta blocker treatment of primary human endothelial cells in vitro decreased hypoxia-mediated HIF-1? 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 ?-AR signal transduction, were investigated. Direct activation of cAMP/PKA pathways did not induce HIF-1? accumulation, and inhibition of PKA did not blunt HIF-1? induction by hypoxia. In contrast, pharmacological inhibition of GRK, or expression of a GRK phosphorylation-deficient ?-AR mutant in cells, blocked hypoxia-mediated HIF-1? accumulation. Mass spectrometry-based quantitative analyses revealed a hypoxia-mediated ?-AR phosphorylation barcode that was different from the classical agonist phosphorylation barcode. These findings indicate that the ?-AR is fundamental to the molecular and physiological responses to hypoxia.

SUBMITTER: Cheong HI

PROVIDER: S-EPMC5161214 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Hypoxia sensing through <b>β</b>-adrenergic receptors.

Cheong Hoi I HI Asosingh Kewal K Stephens Olivia R OR Queisser Kimberly A KA Xu Weiling W Willard Belinda B Hu Bo B Dermawan Josephine Kam Tai JKT Stark George R GR Naga Prasad Sathyamangla V SV Erzurum Serpil C SC

JCI insight 20161222 21

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, ...[more]

PMID: 28018974

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Project description:Stimulation of cardiac ?1A-adrenergic receptors (?1A-AR) has been proposed for treatment of heart failure, since it increases myocardial contractility. We investigated a different mechanism, induction of angiogenesis.Four to 6 weeks after permanent coronary artery occlusion, transgenic rats with cardiomyocyte-specific ?1A-adrenergic receptor overexpression had less remodeling than their nontransgenic littermates, with less fibrosis, hypertrophy and lung weight, and preserved left ventricular ejection fraction and wall stress (all P<0.05). Coronary blood flow, measured with microspheres, increased in the infarct zone in transgenic rats compared with nontransgenic littermates (1.4±0.2 versus 0.5±0.08 mL min(-1) g(-1); P<0.05), which is consistent with angiogenesis, as reflected by a 20% increase in capillary density in the zone adjacent to the infarct. The question arose, how does transgenic overexpression of a gene in cardiomyocytes induce angiogenesis? We identified a paracrine mechanism, whereby vascular endothelial growth factor-A mRNA and protein were increased in isolated transgenic cardiomyocytes and also by nontransgenic littermate cardiomyocytes treated with an ?1A-agonist, resulting in angiogenesis. Conditioned medium from cultured cardiomyocytes treated with an ?1A agonist enhanced human umbilical vein endothelial cell tubule formation, which was blocked by an anti-vascular endothelial growth factor-A antibody. Moreover, improved cardiac function, blood flow, and increased capillary density after chronic coronary artery occlusion in transgenic rats were blocked by either a mitogen ERK kinase (MEK) or a vascular endothelial growth factor-A inhibitor.Cardiomyocyte-specific overexpression of the ?1A-adrenergic receptors resulted in enhanced MEK-dependent cardiomyocyte vascular endothelial growth factor-A expression, which stimulates angiogenesis via a paracrine mechanism involving heterocellular cardiomyocyte/endothelial cell signaling, protecting against remodeling and heart failure after chronic coronary artery occlusion.

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Hypoxia sensing through ?-adrenergic receptors.

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Hypoxia sensing through <b>β</b>-adrenergic receptors.

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