George Hoppe - Academia.edu (original) (raw)

Papers by George Hoppe

Research paper thumbnail of A two-step model of PVL and ROP

Investigative Ophthalmology & Visual Science, Jun 21, 2021

Research paper thumbnail of A Novel Class of Hydrazones Confers Nonhypoxic Activation of HIFα by Potent Inhibition of Proline Hydroxylation

Investigative Ophthalmology & Visual Science, 2011

Research paper thumbnail of Angiotensin Converting Enzyme Dependent And Independent Synthesis Of Angiotensin II In Retina

Investigative Ophthalmology & Visual Science, 2011

Research paper thumbnail of Stabilizing Hepatic HIF-1α Prevents Oxygen-induced Retinopathy

Investigative Ophthalmology & Visual Science, 2014

Research paper thumbnail of 3-Hydroxypyruvate accumulates in the retina of newborn mice exposed to hyperoxia and may contribute to angiostasis

Investigative Ophthalmology & Visual Science, 2018

Research paper thumbnail of Hyperoxia induces glutamine-fuelled anaplerosis in retinal Müller cells

Nature Communications, 2020

Although supplemental oxygen is required to promote survival of severely premature infants, hyper... more Although supplemental oxygen is required to promote survival of severely premature infants, hyperoxia is simultaneously harmful to premature developing tissues such as in the retina. Here we report the effect of hyperoxia on central carbon metabolism in primary mouse Müller glial cells and a human Müller glia cell line (M10-M1 cells). We found decreased flux from glycolysis entering the tricarboxylic acid cycle in Müller cells accompanied by increased glutamine consumption in response to hyperoxia. In hyperoxia, anaplerotic catabolism of glutamine by Müller cells increased ammonium release two-fold. Hyperoxia induces glutamine-fueled anaplerosis that reverses basal Müller cell metabolism from production to consumption of glutamine.

Research paper thumbnail of Hyperoxia Induced Hypomyelination

Biomedicines

We asked whether hyperoxia might induce hypomyelination of the corpus callosum, clinically descri... more We asked whether hyperoxia might induce hypomyelination of the corpus callosum, clinically described as periventricular leukomalacia (PVL) of the severely preterm infant. Mouse pups and their nursing dams were placed in 80% oxygen from P4-P8, then removed to room air until P11. Corpus callosal sections were probed myelin immunofluorescence, tested for myelin basic protein concentration by Western blot, and both glial fibrillary acidic protein levels and apoptosis quantified. Density of corpus callosal capillaries were measured after lectin staining and hypoxia measured by Hypoxyprobe. Numbers of oligodendrocytes were quantified by immunohistochemistry. We next used hypoxiamimesis as a surrogate to hypoxia by comparing cerebral hypoxia inducible factor (HIF) stabilization to hepatic HIF stabilization. Hyperoxia induced hypomyelination and a reduction of corpus callosal capillaries. Hyperoxia decreased numbers of oligodendrocytes with an increase in corpus callosal fibrosis and apopto...

Research paper thumbnail of Monocyte Adhesion to Retinal Pigment Epithelium Cells

Investigative Ophthalmology & Visual Science, 2006

Research paper thumbnail of Comparison of Biphasic vs Static Oxygen Saturation Targets Among Infants With Retinopathy of Prematurity

JAMA Ophthalmology, 2019

(SUPPORT) demonstrated that static low oxygen saturation decreased retinopathy of prematurity (RO... more (SUPPORT) demonstrated that static low oxygen saturation decreased retinopathy of prematurity (ROP) but increased mortality compared with static high oxygen saturation cohorts. OBJECTIVE To compare outcomes of a biphasic oxygen protocol with static targets recommended by SUPPORT. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study comparing biphasic vs static standards 41 months prior to and 42 months after a change from biphasic to static SUPPORT standards at a level III neonatal intensive care unit (Fairview Hospital, Cleveland, Ohio). The study included infants born at a corrected gestational age (CGA) of 31 weeks or younger or birth weight 1500 g or less. Data were analyzed between August 2010 and July 2017. INTERVENTIONS The pre-SUPPORT group underwent biphasic protocol target saturations of 85% to 92% at younger than 34 weeks' CGA and greater than 95% at 34 weeks' CGA or older. The post-SUPPORT group underwent a constant 91% to 95% target. MAIN OUTCOMES AND MEASURES Primary outcome was incidence of type 1 ROP. Secondary outcomes were incidence of any ROP, time to full vascularization, and mortality. RESULTS Of 596 eligible infants, 562 were included in ophthalmic analysis. Three hundred three patients were boys (54%); 399 were white (71%), 87 were black (15%), and 76 were of other or unknown race/ethnicity (14%). Mean (SD) CGA and birth weight were 29 (2) weeks and 1151 (346) g, respectively. Any ROP overall increased (53 [20%] pre-SUPPORT vs n = 86 [28%] post-SUPPORT; absolute difference, 8%; 95% CI, 1%-15%; odds ratio, 1.6; 95% CI, 1.05-2.3; P = .03). Type 1 ROP increased in the post-SUPPORT era (n = 6 [2%] pre-SUPPORT vs n = 18 [6%] post-SUPPORT; absolute difference, 4%; 95% CI, 0.4%-7%; odds ratio, 2.7; 95% CI, 1.05-6.9; P = .03). There was a delay in vascularization in the post-SUPPORT group (n = 6 [2%] pre-SUPPORT vs n = 18 [6%] post-SUPPORT; absolute difference, 4%; 95% CI, 0.4%-7%; P = .03). CONCLUSIONS AND RELEVANCE Compared with static oxygen standards, biphasic oxygen targets are associated with decreased incidence and severity of ROP without increasing mortality.

Research paper thumbnail of Glutathione as a Second Messenger of Oxidation: Hsc70 Is a Substrate of Glutaredoxin-1

Research paper thumbnail of Rank Order of Small Molecule Induced Hypoxiamimesis to Prevent Retinopathy of Prematurity

Frontiers in Cell and Developmental Biology, 2020

Here we rank order small molecule inhibitors of hypoxia inducible factor (HIF) prolyl hydroxylase... more Here we rank order small molecule inhibitors of hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) using severity of oxygen induced retinopathy (OIR) as an outcome measure. Dose response analyses in cell cultures of hepatoma (Hep3B), retinal Müller cells (MIO-M1) and primary retinal endothelial cells were conducted to evaluate potency by comparing dose to HIF-1,2 protein levels by western blotting. In vivo dose response was determined using the luciferase-transgene HIF reporter (luc-ODD). Each compound was placed in rank order by their ability to reduce neovascularization and capillary drop out in the OIR mouse model. An Epas1 KO confined to retinal Müller cells was used to determine whether successful protection by HIF stabilization requires HIF-2. Two candidate small molecules can prevent OIR by stabilizing HIF-1 to prevent oxygen induced growth attenuation and vascular obliteration. Müller cell HIF-2, the mediator of pathologic retinal angiogenesis, is not required for protection. The lack of dependence on Müller cell HIF-2 predicts that inhibition of HIF PHD will not drive pathological angiogenesis.

Research paper thumbnail of Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity

Research paper thumbnail of Müller Cell HIF-2 is Not Required for Protection Against Oxygen Induced Retinopathy by Prolyl Hydroxylase Inhibition

Research paper thumbnail of Peroxisome Proliferator-Activated Receptor Gamma Pioglitazone Reduces Secretion of Interleukin-8 by Retinal Pigment Epithelium Cells Under Hyperglycemic Stress

Investigative Ophthalmology & Visual Science, 2008

Research paper thumbnail of Incidence of ROP After SUPPORT

Investigative Ophthalmology & Visual Science, 2016

Research paper thumbnail of HIF stabilization in the liver prevents ROP by secreting hepatokines capable of promoting metabolic switch in retinal endothelium

Investigative Ophthalmology & Visual Science, 2015

Research paper thumbnail of Downregulation of Major Non-Histone Nuclear Protein Hmgb1 Hypersensitizes Neurons to UV-Light-Induced DNA Damage

Investigative Ophthalmology & Visual Science, 2007

Research paper thumbnail of Identification of High Mobility Group Protein B1, a DNA–Binding Structural Chromosomal Protein, as a Novel Substrate of RPE Glutaredoxin

Investigative Ophthalmology & Visual Science, 2005

Research paper thumbnail of Glutaredoxin Reduces Chaperone Activity via Deglutathionylation of Hsc70

Investigative Ophthalmology & Visual Science, 2004

Research paper thumbnail of Comparison of Neurodevelopmental Outcomes In Two Retinopathy of Prematurity (ROP) Cohorts: Standard vs. Revised Oxygen Saturation Protocol Groups

Investigative Ophthalmology & Visual Science, 2012

Research paper thumbnail of A two-step model of PVL and ROP

Investigative Ophthalmology & Visual Science, Jun 21, 2021

Research paper thumbnail of A Novel Class of Hydrazones Confers Nonhypoxic Activation of HIFα by Potent Inhibition of Proline Hydroxylation

Investigative Ophthalmology & Visual Science, 2011

Research paper thumbnail of Angiotensin Converting Enzyme Dependent And Independent Synthesis Of Angiotensin II In Retina

Investigative Ophthalmology & Visual Science, 2011

Research paper thumbnail of Stabilizing Hepatic HIF-1α Prevents Oxygen-induced Retinopathy

Investigative Ophthalmology & Visual Science, 2014

Research paper thumbnail of 3-Hydroxypyruvate accumulates in the retina of newborn mice exposed to hyperoxia and may contribute to angiostasis

Investigative Ophthalmology & Visual Science, 2018

Research paper thumbnail of Hyperoxia induces glutamine-fuelled anaplerosis in retinal Müller cells

Nature Communications, 2020

Although supplemental oxygen is required to promote survival of severely premature infants, hyper... more Although supplemental oxygen is required to promote survival of severely premature infants, hyperoxia is simultaneously harmful to premature developing tissues such as in the retina. Here we report the effect of hyperoxia on central carbon metabolism in primary mouse Müller glial cells and a human Müller glia cell line (M10-M1 cells). We found decreased flux from glycolysis entering the tricarboxylic acid cycle in Müller cells accompanied by increased glutamine consumption in response to hyperoxia. In hyperoxia, anaplerotic catabolism of glutamine by Müller cells increased ammonium release two-fold. Hyperoxia induces glutamine-fueled anaplerosis that reverses basal Müller cell metabolism from production to consumption of glutamine.

Research paper thumbnail of Hyperoxia Induced Hypomyelination

Biomedicines

We asked whether hyperoxia might induce hypomyelination of the corpus callosum, clinically descri... more We asked whether hyperoxia might induce hypomyelination of the corpus callosum, clinically described as periventricular leukomalacia (PVL) of the severely preterm infant. Mouse pups and their nursing dams were placed in 80% oxygen from P4-P8, then removed to room air until P11. Corpus callosal sections were probed myelin immunofluorescence, tested for myelin basic protein concentration by Western blot, and both glial fibrillary acidic protein levels and apoptosis quantified. Density of corpus callosal capillaries were measured after lectin staining and hypoxia measured by Hypoxyprobe. Numbers of oligodendrocytes were quantified by immunohistochemistry. We next used hypoxiamimesis as a surrogate to hypoxia by comparing cerebral hypoxia inducible factor (HIF) stabilization to hepatic HIF stabilization. Hyperoxia induced hypomyelination and a reduction of corpus callosal capillaries. Hyperoxia decreased numbers of oligodendrocytes with an increase in corpus callosal fibrosis and apopto...

Research paper thumbnail of Monocyte Adhesion to Retinal Pigment Epithelium Cells

Investigative Ophthalmology & Visual Science, 2006

Research paper thumbnail of Comparison of Biphasic vs Static Oxygen Saturation Targets Among Infants With Retinopathy of Prematurity

JAMA Ophthalmology, 2019

(SUPPORT) demonstrated that static low oxygen saturation decreased retinopathy of prematurity (RO... more (SUPPORT) demonstrated that static low oxygen saturation decreased retinopathy of prematurity (ROP) but increased mortality compared with static high oxygen saturation cohorts. OBJECTIVE To compare outcomes of a biphasic oxygen protocol with static targets recommended by SUPPORT. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study comparing biphasic vs static standards 41 months prior to and 42 months after a change from biphasic to static SUPPORT standards at a level III neonatal intensive care unit (Fairview Hospital, Cleveland, Ohio). The study included infants born at a corrected gestational age (CGA) of 31 weeks or younger or birth weight 1500 g or less. Data were analyzed between August 2010 and July 2017. INTERVENTIONS The pre-SUPPORT group underwent biphasic protocol target saturations of 85% to 92% at younger than 34 weeks' CGA and greater than 95% at 34 weeks' CGA or older. The post-SUPPORT group underwent a constant 91% to 95% target. MAIN OUTCOMES AND MEASURES Primary outcome was incidence of type 1 ROP. Secondary outcomes were incidence of any ROP, time to full vascularization, and mortality. RESULTS Of 596 eligible infants, 562 were included in ophthalmic analysis. Three hundred three patients were boys (54%); 399 were white (71%), 87 were black (15%), and 76 were of other or unknown race/ethnicity (14%). Mean (SD) CGA and birth weight were 29 (2) weeks and 1151 (346) g, respectively. Any ROP overall increased (53 [20%] pre-SUPPORT vs n = 86 [28%] post-SUPPORT; absolute difference, 8%; 95% CI, 1%-15%; odds ratio, 1.6; 95% CI, 1.05-2.3; P = .03). Type 1 ROP increased in the post-SUPPORT era (n = 6 [2%] pre-SUPPORT vs n = 18 [6%] post-SUPPORT; absolute difference, 4%; 95% CI, 0.4%-7%; odds ratio, 2.7; 95% CI, 1.05-6.9; P = .03). There was a delay in vascularization in the post-SUPPORT group (n = 6 [2%] pre-SUPPORT vs n = 18 [6%] post-SUPPORT; absolute difference, 4%; 95% CI, 0.4%-7%; P = .03). CONCLUSIONS AND RELEVANCE Compared with static oxygen standards, biphasic oxygen targets are associated with decreased incidence and severity of ROP without increasing mortality.

Research paper thumbnail of Glutathione as a Second Messenger of Oxidation: Hsc70 Is a Substrate of Glutaredoxin-1

Research paper thumbnail of Rank Order of Small Molecule Induced Hypoxiamimesis to Prevent Retinopathy of Prematurity

Frontiers in Cell and Developmental Biology, 2020

Here we rank order small molecule inhibitors of hypoxia inducible factor (HIF) prolyl hydroxylase... more Here we rank order small molecule inhibitors of hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) using severity of oxygen induced retinopathy (OIR) as an outcome measure. Dose response analyses in cell cultures of hepatoma (Hep3B), retinal Müller cells (MIO-M1) and primary retinal endothelial cells were conducted to evaluate potency by comparing dose to HIF-1,2 protein levels by western blotting. In vivo dose response was determined using the luciferase-transgene HIF reporter (luc-ODD). Each compound was placed in rank order by their ability to reduce neovascularization and capillary drop out in the OIR mouse model. An Epas1 KO confined to retinal Müller cells was used to determine whether successful protection by HIF stabilization requires HIF-2. Two candidate small molecules can prevent OIR by stabilizing HIF-1 to prevent oxygen induced growth attenuation and vascular obliteration. Müller cell HIF-2, the mediator of pathologic retinal angiogenesis, is not required for protection. The lack of dependence on Müller cell HIF-2 predicts that inhibition of HIF PHD will not drive pathological angiogenesis.

Research paper thumbnail of Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity

Research paper thumbnail of Müller Cell HIF-2 is Not Required for Protection Against Oxygen Induced Retinopathy by Prolyl Hydroxylase Inhibition

Research paper thumbnail of Peroxisome Proliferator-Activated Receptor Gamma Pioglitazone Reduces Secretion of Interleukin-8 by Retinal Pigment Epithelium Cells Under Hyperglycemic Stress

Investigative Ophthalmology & Visual Science, 2008

Research paper thumbnail of Incidence of ROP After SUPPORT

Investigative Ophthalmology & Visual Science, 2016

Research paper thumbnail of HIF stabilization in the liver prevents ROP by secreting hepatokines capable of promoting metabolic switch in retinal endothelium

Investigative Ophthalmology & Visual Science, 2015

Research paper thumbnail of Downregulation of Major Non-Histone Nuclear Protein Hmgb1 Hypersensitizes Neurons to UV-Light-Induced DNA Damage

Investigative Ophthalmology & Visual Science, 2007

Research paper thumbnail of Identification of High Mobility Group Protein B1, a DNA–Binding Structural Chromosomal Protein, as a Novel Substrate of RPE Glutaredoxin

Investigative Ophthalmology & Visual Science, 2005

Research paper thumbnail of Glutaredoxin Reduces Chaperone Activity via Deglutathionylation of Hsc70

Investigative Ophthalmology & Visual Science, 2004

Research paper thumbnail of Comparison of Neurodevelopmental Outcomes In Two Retinopathy of Prematurity (ROP) Cohorts: Standard vs. Revised Oxygen Saturation Protocol Groups

Investigative Ophthalmology & Visual Science, 2012