Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury

Schneider, Martin; Geyte, Katie Van; Fraisl, Peter; Kiss, Judit; Aragonés, Julián; Mazzone, Massimiliano; Mairbäurl, Heimo; Bock, Katrien De; Jeoung, Nam Ho; Mollenhauer, Martin; Γεωργιάδου, Μαρία; Bishop, Tammie; Roncal, Carmen; Sutherland, Andrew; Jordan, Bénédicte F.; Gallez, Bernard; Weitz, Jürgen; Harris, Robert A.; Maxwell, Patrick H.; Baes, Myriam; Ratcliffe, Peter J.; Carmeliet, Peter

doi:10.1053/j.gastro.2009.09.057

Cited by 113 publications

(117 citation statements)

References 30 publications

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“…Pyruvate dehydrogenase kinase 1, a key regulator for glycolysis, did not change in the setting of pMCAO, although it has been established as an important mediator of resistance to muscle and liver ischemia in mice lacking PHD-1 (Aragones et al, 2008;Schneider et al, 2010). However, those tissues have a huge potential in upregulating their gylcolytic metabolism during hypoxia/ischemia, which is not the case for the brain, and it seems unlikely that increased glycolysis is a potential mechanism of PHD/HIF-related neuroprotection.…”

Section: Discussionmentioning

confidence: 93%

Neuroprotection by Dimethyloxalylglycine following Permanent and Transient Focal Cerebral Ischemia in Rats

Nagel

Papadakis

Chen

et al. 2010

J Cereb Blood Flow Metab

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Dimethyloxalylglycine (DMOG) is an inhibitor of prolyl-4-hydroxylase domain (PHD) enzymes that regulate the stability of hypoxia-inducible factor (HIF). We investigated the effect of DMOG on the outcome after permanent and transient middle cerebral artery occlusion (p/tMCAO) in the rat. Before and after pMCAO, rats were treated with 40 mg/kg, 200 mg/kg DMOG, or vehicle, and with 40 mg/kg or vehicle after tMCAO. Serial magnetic resonance imaging (MRI) was performed to assess infarct evolution and regional cerebral blood flow (rCBF). Both doses significantly reduced infarct volumes, but only 40 mg/kg improved the behavior after 24 hours of pMCAO. Animals receiving 40 mg/kg were more likely to maintain rCBF values above 30% from the contralateral hemisphere within 24 hours of pMCAO. DMOG after tMCAO significantly reduced the infarct volumes and improved behavior at 24 hours and 8 days and also improved the rCBF after 24 hours. A consistent and significant upregulation of both mRNA and protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) was associated with the observed neuroprotection, although this was not consistently related to HIF-1a levels at 24 hours and 8 days. Thus, DMOG afforded neuroprotection both at 24 hours after pMCAO and at 24 hours and 8 days after tMCAO. This effect was associated with an increase of VEGF and eNOS and was mediated by improved rCBF after DMOG treatment.

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Section: Discussionmentioning

confidence: 93%

Neuroprotection by Dimethyloxalylglycine following Permanent and Transient Focal Cerebral Ischemia in Rats

Nagel

Papadakis

Chen

et al. 2010

J Cereb Blood Flow Metab

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“…The generation of PHD knockout mice has been described elsewhere (13,17,18). All animal experiments were approved by the ethical commission of the local government.…”

Section: Mouse Modelsmentioning

confidence: 99%

“…Recent studies applying genetic loss-of-function approaches indicated that PHD enzymes carry out specific and nonredundant in vivo functions. Loss of PHD1 specifically alters the mitochondrial energy metabolism of skeletal muscle (12) or liver cells (13), thus increasing their hypoxic survival. Furthermore, loss of PHD1 increases the intestinal barrier function and is protective against experimental colitis (1,14).…”

mentioning

confidence: 99%

Loss of the Oxygen Sensor PHD3 Enhances the Innate Immune Response to Abdominal Sepsis

Kiss

Mollenhauer

Walmsley

et al. 2012

The Journal of Immunology

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Hypoxia and HIFs (HIF-1α and HIF-2α) modulate innate immune responses in the setting of systemic inflammatory responses and sepsis. The HIF prolyl hydroxylase enzymes PHD1, PHD2 and PHD3 regulate the mammalian adaptive response to hypoxia; however, their significance in the innate immune response has not been elucidated. We demonstrate in this study that deficiency of PHD3 (PHD3−/−) specifically shortens the survival of mice subjected to various models of abdominal sepsis because of an overwhelming innate immune response, leading to premature organ dysfunction. By contrast, this phenotype was absent in mice deficient for PHD1 (PHD1−/−) or PHD2 (PHD2+/−). In vivo, plasma levels of proinflammatory cytokines were enhanced, and recruitment of macrophages to internal organs was increased in septic PHD3-deficient mice. Reciprocal bone marrow transplantation in sublethally irradiated mice revealed that enhanced susceptibility of PHD3-deficient mice to sepsis-related lethality was specifically caused by loss of PHD3 in myeloid cells. Several in vitro assays revealed enhanced cytokine production, migration, phagocytic capacity, and proinflammatory activation of PHD3-deficient macrophages. Increased proinflammatory activity of PHD3-deficient macrophages occurred concomitantly with enhanced HIF-1α protein stabilization and increased NF-κB activity, and interference with the expression of HIF-1α or the canonical NF-κB pathway blunted their proinflammatory phenotype. It is concluded that impairment of PHD3 enzyme function aggravates the clinical course of abdominal sepsis via HIF-1α– and NF-κB–mediated enhancement of the innate immune response.

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“…Schneider et al exposed liver allografts to 90 min of warm ischemia by clamping of the portal vessels with 8 h of reperfusion in PHD1 (À/À) mice (30). The authors demonstrated resistance to ischemia in the PHD1 (À/À) mice as assessed by quantifying apoptosis, necrosis and mouse survival.…”

Section: Livermentioning

confidence: 99%

The Role of Hypoxia-Inducible Factors in Organ Donation and Transplantation: The Current Perspective and Future Opportunities

Akhtar

Sutherland

Huang

et al. 2014

American Journal of Transplantation

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Hypoxia‐inducible factors are the universal cellular oxygen‐sensitive transcription factors that activate a number of hypoxia responsive genes, some of which are responsible for protective cellular functions. During organ donation, allografts are exposed to significant periods of hypoxia and ischemia. Exploiting this pathway during donor management and organ preservation could prevent and reduce allograft injury and improve the outcomes of organ transplantation. We review the evidence on this pathway in organ preservation, drawing on experimental studies on donor management and ischemia reperfusion injury focusing on kidney, liver, cardiac and lung transplantation. We review the major technical and experimental challenges in exploring this pathway and suggest potential future avenues for research.

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Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury

Abstract: Loss of PHD1 provided tolerance of hepatocytes to acute hypoxia and protected them against I/R-damage. Short-term inhibition of PHD1 is a novel therapeutic approach to reducing or preventing I/R-induced liver injury.

Cited by 113 publications

References 30 publications

Neuroprotection by Dimethyloxalylglycine following Permanent and Transient Focal Cerebral Ischemia in Rats

Neuroprotection by Dimethyloxalylglycine following Permanent and Transient Focal Cerebral Ischemia in Rats

Loss of the Oxygen Sensor PHD3 Enhances the Innate Immune Response to Abdominal Sepsis

The Role of Hypoxia-Inducible Factors in Organ Donation and Transplantation: The Current Perspective and Future Opportunities

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