Genomes and Genes
Hypoxia-Inducible Factor 1 and Oxygen Homeostasis
Principal Investigator: Gregg Semenza
Abstract: Humans and other mammals have a constant and absolute requirement for oxygen and tissue oxygenation is maintained within a narrow range. In many disease states, however, oxygen homeostasis is disrupted and hypoxia/ischemia is an important factor contributing to the pathophysiology of ischemic cardiovascular disease, chronic lung disease, and other major causes of mortality. The broad, long-term goal of the proposed research is to increase our understanding of the role of the transcriptional regulator hypoxia-inducible factor 1 (HIF-1) in the maintenance of oxygen homeostasis. In particular, the studies that will be performed in years 10-14 of R01HL55338 will focus on the role of HIF-1 as a master regulator of tissue vascularization. The knowledge gained from the proposed experiments will be relevant to the treatment of disorders associated with altered vascularization, particularly ischemic cardiovascular disease. The specific aims are: 1. To determine the role of HIF-1 in the vascular response to tissue ischemia. We will test the hypothesis that HIF-1 activity within ischemic muscle promotes angiogenic growth factor gene expression and vascularization. 2. To investigate the role of HlF-1 in vascular progenitor cells. We will test the hypothesis that HIF-1 activity in endothelial progenitor cells (EPCs) promotes their differentiation, recruitment, and survival, and stimulates EPC-mediated vascular remodeling in ischemic tissue. To delineate transcriptional networks regulated by HIF-1 in human arterial endothelial and smooth muscle cells. We will test the hypothesis that HIF-1 controls the expression of distinct batteries of genes in a cell type- specific manner and that this regulation is mediated via either direct DMA binding or indirectly via the regulation of other transcription factors.
Funding Period: 1996-03-01 - 2010-05-31
more information: NIH RePORT
- The role of hypoxia-inducible factors in oxygen sensing by the carotid bodyGregg L Semenza
Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Adv Exp Med Biol 758:1-5. 2012..Thus, IH disrupts the balance between HIF-1-dependent pro-oxidant and HIF-2-dependent anti-oxidant activities, and this loss of redox homeostasis underlies the pathogenesis of autonomic morbidities associated with IH...
- Age-dependent impairment of HIF-1alpha expression in diabetic mice: Correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cellsLixin Liu
Section of Surgical Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
J Cell Physiol 217:319-27. 2008..Thus, HIF-1alpha gene therapy corrects the age-dependent impairment of HIF-1alpha expression, angiogenic cytokine expression, and CACs that contribute to the age-dependent impairment of wound healing in db/db mice...
- Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2Nanduri R Prabhakar
Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, Illinois, USA
Physiol Rev 92:967-1003. 2012..In contrast, intermittent hypoxia, which occurs in association with sleep-disordered breathing, results in an imbalance between HIF-1α and HIF-2α that causes oxidative stress, leading to cardiorespiratory pathology...
- Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejectionXinguo Jiang
Department of Medicine, VA Palo Alto Health Care System Stanford University School of Medicine, Stanford, California, USA
J Clin Invest 121:2336-49. 2011..This study demonstrates that a therapy that enhances vascular integrity during acute rejection may promote graft health and prevent chronic rejection...
- Vascular responses to hypoxia and ischemiaGregg L Semenza
Institute for Cell Engineering, Departments of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Arterioscler Thromb Vasc Biol 30:648-52. 2010..Impairment of HIF-1-dependent responses to hypoxia is a major factor contributing to the impaired vascular responses to ischemia that are associated with aging and diabetes...
- HIF-1: upstream and downstream of cancer metabolismGregg L Semenza
Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Broadway Research Building, Suite 671, 733 North Broadway, Baltimore, MD 21205, United States
Curr Opin Genet Dev 20:51-6. 2010..Many metabolic abnormalities in cancer cells increase HIF-1 activity. As a result, a feed-forward mechanism can be activated that drives HIF-1 activation and may promote tumor progression...
- Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodellingSergio Rey
Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Broadway Research Building, Suite 671, 733 N Broadway, Baltimore, MD 21205, USA
Cardiovasc Res 86:236-42. 2010..This review will focus on the pivotal role of HIF-1 in vascular homeostasis, the involvement of HIF-1 in vascular diseases, and recent advances in targeting HIF-1 for therapy in preclinical models...
- HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injuryRena Feinman
UMDNJ New Jersey Medical School, Dept of Surgery, Newark, 07103, USA
Am J Physiol Gastrointest Liver Physiol 299:G833-43. 2010..Consequently, these results provide unique information on the initiating events in trauma-hemorrhagic shock-induced ALI and MODS as well as potential therapeutic insights...
- Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioningGregg L Semenza
Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Biochim Biophys Acta 1813:1263-8. 2011..HIF-1-dependent regulation of mitochondrial metabolism may also contribute to the protective effects of ischemic preconditioning. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection...
- Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injuryKolenkode B Kannan
Dept of Surgery, UMDNJ New Jersey Medical School, Newark, 07103, USA
Am J Physiol Gastrointest Liver Physiol 300:G853-61. 2011..However, the duration and severity of the gut I/R insult dictate whether HIF-1 plays a gut-protective or deleterious role...
- Nitric oxide prevents axonal degeneration by inducing HIF-1-dependent expression of erythropoietinSanjay C Keswani
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Proc Natl Acad Sci U S A 108:4986-90. 2011..Our results indicate that NO→HIF-1→EPO signaling represents an adaptive mechanism that protects against axonal degeneration...
- Metabolic reprogramming by HIF-1 promotes the survival of bone marrow-derived angiogenic cells in ischemic tissueSergio Rey
Institute for Cell Engineering, Johns Hopkins University Schoolof Medicine, Baltimore, MD, USA
Blood 117:4988-98. 2011....
- T-cell activation under hypoxic conditions enhances IFN-gamma secretionJessica Roman
University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642 8692, USA
Am J Respir Cell Mol Biol 42:123-8. 2010..We conclude that hypoxia is a previously underappreciated modulator of effector cytokine secretion in CD4(+) T cells...
- Enhanced interferon-gamma gene expression in T Cells and reduced ovalbumin-dependent lung eosinophilia in hypoxia-inducible factor-1-alpha-deficient miceJia Guo
Division of Pulmonary and Critical Care, University of Rochester Medical Center, Rochester 14642, NY, USA
Int Arch Allergy Immunol 149:98-102. 2009..Hypoxia-inducible factor-1alpha (HIF-1alpha) in particular controls the expression of many hypoxia regulated genes, but whether HIF-1alpha directly contributes to allergen-driven immune responses is not known...
- Tumor metabolism: cancer cells give and take lactateGregg L Semenza
Vascular Program, Institute for Cell Engineering, Department of Pediatrics, John Hopkins University School of Medicine, Baltimore, Maryland, USA
J Clin Invest 118:3835-7. 2008..MCT1 expression was detected exclusively in nonhypoxic regions of human cancer biopsy samples, and in combination, these data suggest that MCT1 inhibition holds potential as a novel cancer therapy...
- Synergistic effect of HIF-1alpha gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemiaSergio Rey
Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Proc Natl Acad Sci U S A 106:20399-404. 2009..Thus, HIF-1alpha gene therapy increases homing of BMDACs to ischemic muscle, whereas HIF-1 induction in BMDACs enhances their adhesion to vascular endothelium, leading to synergistic effects of combined therapy on tissue perfusion...
- The expanding universe of hypoxiaHuafeng Zhang
Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
J Mol Med (Berl) 86:739-46. 2008..In this meeting report, we summarize major developments in the field that were presented at the 2008 Keystone Symposium on Cellular, Physiological, and Pathogenic Responses to Hypoxia...
- Mitochondrial autophagy: life and breath of the cellGregg L Semenza
Vascular Program, Institute for Cell Engineering, Department of Pediatrics, McKusick Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Autophagy 4:534-6. 2008..These studies indicate that mitochondrial autophagy represents an adaptive metabolic response to hypoxia that is necessary to maintain redox homeostasis and cell survival...
- Ca2+/calmodulin kinase-dependent activation of hypoxia inducible factor 1 transcriptional activity in cells subjected to intermittent hypoxiaGuoxiang Yuan
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA
J Biol Chem 280:4321-8. 2005..These observations suggest that IH induces HIF-1 transcriptional activity via a novel signaling pathway involving CaM kinase...
- Constitutively active HIF-1alpha improves perfusion and arterial remodeling in an endovascular model of limb ischemiaTarak H Patel
The Russell H Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Cardiovasc Res 68:144-54. 2005..We analyzed the effect of intramuscular (i.m.) delivery of AdCA5, an adenovirus encoding a constitutively active form of the HIF-1alpha subunit, in a novel model of limb ischemia...
- Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptorDavid Zagzag
Microvascular and Molecular Neuro Oncology Laboratory, New York, New York, USA
Cancer Res 65:6178-88. 2005....
- Hypoxia-inducible factor 1alpha polymorphism and coronary collaterals in patients with ischemic heart diseaseJon R Resar
Division of Cardiology, The Johns Hopkins University School of Medicine, Blalock 524, 600 North Wolfe St, Baltimore, MD 21287, USA
Chest 128:787-91. 2005..Hypoxia inducible factor 1 (HIF-1), a transcriptional activator that functions as a master regulator of oxygen homeostasis, is one possible genetic factor that could play an important role in modulating collateral development...
- Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1alphaJianguo Li
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Physiol Genomics 25:450-7. 2006....
- Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular Ca2+ in pulmonary arterial smooth muscle cellsJian Wang
Division of Pulmonary and Critical Care Medicine, Institute for Cell Engineering, Baltimore, MD, USA
Circ Res 98:1528-37. 2006....
- HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytesLarissa A Shimoda
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, JHAAC 4A 52, Baltimore, MD 21224, USA
Am J Physiol Lung Cell Mol Physiol 291:L941-9. 2006....
- Hypoxia-inducible factor-1 deficiency results in dysregulated erythropoiesis signaling and iron homeostasis in mouse developmentDonghoon Yoon
Hematology Section, University of Utah, Salt Lake City, Utah 84132, USA
J Biol Chem 281:25703-11. 2006..These results identify a novel role for HIF-1 in the regulation of iron homeostasis and reveal unexpected regulatory differences in Epo/EpoR signaling in yolk sac and embryonic erythropoiesis...
- Partial rescue of defects in Cited2-deficient embryos by HIF-1alpha heterozygosityBing Xu
Department of Pharmacology and Cancer Center, Case Western Reserve University, School of Medicine, W319, Cleveland, OH 44106, USA
Dev Biol 301:130-40. 2007..These findings suggest that a precise level of HIF-1 transcriptional activity critical for normal development is triggered by differential hypoxia and regulated through feedback inhibition by Cited2...
- Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1Gregg L Semenza
Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Biochem J 405:1-9. 2007....
- Spermidine/spermine-N1-acetyltransferase 2 is an essential component of the ubiquitin ligase complex that regulates hypoxia-inducible factor 1alphaJin Hyen Baek
Vascular Biology Program, Institute for Cell Engineering, Department of Pediatrics, and McKusick Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
J Biol Chem 282:23572-80. 2007..Multivalent interactions by SSAT2 provide a mechanism to ensure efficient complex formation, which is necessary for the extremely rapid ubiquitination and degradation of HIF-1alpha that is observed in oxygenated cells...
- Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemiaMarta Bosch-Marce
Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Circ Res 101:1310-8. 2007..These results indicate that HIF-1 activity is necessary and sufficient for the mobilization of angiogenic cells and that HIF-1alpha gene therapy can counteract the pathological effects of aging in a mouse model of limb ischemia...
- Endothelin-1 mediates hypoxia-induced inhibition of voltage-gated K+ channel expression in pulmonary arterial myocytesE Miles Whitman
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA
Am J Physiol Lung Cell Mol Physiol 294:L309-18. 2008..These results suggest that the inhibition of K(v) channel expression and rise in [Ca(2+)](i) during chronic hypoxia may be the result of HIF-1-dependent induction of ET-1...
- Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1Dominador J Manalo
Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Blood 105:659-69. 2005....