Hypoxia-Inducible Factors in Physiology and Medicine Gregg L. Semenza, M.D., Ph.D. Vascular Program, Institute for Cell Engineering; Departments of Genetic Medicine, Pediatrics, Oncology, Medicine, Radiation Oncology, and Biological Chemistry; Johns Hopkins University School of Medicine Baltimore, Maryland USA
Oxygen Homeostasis: A Balancing Act O 2 Supply Blood O 2 Demand Heart Blood Vessels Lungs CNS Hypoxia-Inducible Factors
Control of Red Blood Cell Production Cardiovascular Disease Cancer
Control of Red Blood Cell Production Cardiovascular Disease Cancer
Erythropoietin Controls Red Blood Cell Production Erythropoietin (EPO) Bone marrow O 2 delivery to every cell In the body
Erythropoietin Controls Red Blood Cell Production Chronic Kidney Disease Erythropoietin (EPO) Bone marrow O 2 delivery to every cell In the body
Erythropoietin Controls Red Blood Cell Production What Controls Erythropoietin Production? ? Chronic Kidney Disease Erythropoietin (EPO) Bone marrow O 2 delivery to every cell In the body
Hypoxia-Inducible Factor 1 (HIF-1) Binds to the EPO Gene and Activates Transcription Hypoxia Response HATs Element G. L. Semenza and G. L. Wang, Mol. Cell. Biol. 12: 5447, 1992 G. L. Wang and G. L. Semenza, J. Biol. Chem . 270: 1230, 1995 G. L. Wang et al. Proc. Natl. Acad. Sci. USA 92: 5510, 1995
HIF-1 α is Regulated by Oxygen-dependent Hydroxylation CO 2 + succinate O 2 + α -ketoglutarate PHDs = Prolyl Hydroxylase Domain proteins target HIF-1 α for destruction when O 2 is available.
HIF-1 α Protein Accumulates in Response to Hypoxia Leading to Increased Transcription of HIF-1 Target Genes B.-H. Jiang et al. Am. J. Physiol. 1996;271:C1172 % O 2 Venous P O 2 Arterial P O 2 ~40 mm Hg ~100 mm Hg
HIF-1 Mediates Homeostatic Responses to Reduced O 2 Levels > 4,000 Target Genes
HIF-1 α is Required for Development of the Circulatory System Yolk sac Heart Blood +/+ -/- Blood Embryo Blood Vessels +/+ -/- N. V. Iyer et al., Genes Dev. 12: 149, 1998 D. Yoon et al., J. Biol. Chem. 281:25703, 2006
HIF-1 α, HIF-2 α and HIF-3 α Heterodimerize with HIF-1 β and Activate Gene Transcription HIF-1 HIF-2 HIF-3 H H H H H H I I I I I I F F F F F F 1 1 2 1 3 1 α β α β α β All nucleated Certain cell Certain cell cell types of types of types of ~all metazoan vertebrate vertebrate species species species
Congenital Polycythemia (Too Many Red Cells) is Caused by Mutations in the HIF Pathway Red blood cell production EPOR Type 4 HIF2 α EPO Gain of Function Type 1 EPOR HIF-1 α Gain of Function HIF-2 α Type 2 O 2 PHD2 VHL HIF- α Loss of function Type 3 Pro-OH PHD2 VHL Loss of function HIF- α Pro-OH Lys-Ubi n HIF degradation
Control of Red Blood Cell Production Cardiovascular Disease Cancer
Cardiovascular Disease is the Leading Cause of Death In the Industrialized World CORONARY ARTERY CHEST PAIN HEART ATTACK stenosis PERIPHERAL ARTERY LEG PAIN AMPUTATION
Cardiovascular Disease is the Leading Cause of Death In the Industrialized World CORONARY ARTERY CHEST PAIN HEART ATTACK PERIPHERAL ARTERY LEG PAIN AMPUTATION
Critical Limb Ischemia: End-Stage Peripheral Arterial Disease Critical Limb Ischemia stenosis Perfusion is not sufficient to maintain tissue viability, leading to: Ischemic pain at rest collateral Ischemic ulcers Gangrene Limb amputation
Analysis of Vascularization after Femoral Artery Ligation in Wild-type (WT) and Heterozygous HIF-1 α− Null (HET) Mice 1.20 Ischemic:Non-ischemic Limb Perfusion Ratio Laser Doppler Perfusion Imaging 1.00 0.80 WT 2 mon old HET 0.60 WT 8 mon old HET 0.40 WT 20 mon old HET 0.20 0.00 Pre- Post- 3 7 14 21 28 35 Op Op Time (days) M. Bosch-Marcé et al. Circ. Res. 2007;101:1310
Additive Effects of Aging and Hif1a Genotype on Limb Salvage 120 Limb salvage 100 BAA/necrosis % of Animals in Group 80 AAA 60 40 20 0 WT HET WT HET WT HET ( n = 10) ( n = 9) ( n = 10) ( n = 15) ( n = 7) ( n = 8) 2 mon old 8 mon old 20 mon old M. Bosch-Marcé et al., Circ. Res. 2007;101:1310
Effects of Aging and Hif1a Genotype on Ischemia-induced HIF-1 α Protein Levels 2-month-old 8-month-old 20-month-old WT HET WT HET WT HET NIS ISC NIS ISC NIS ISC NIS ISC NIS ISC NIS ISC HIF-1 α β -actin M. Bosch-Marcé et al., Circ. Res. 2007;101:1310
Improved Recovery of Perfusion in Mice by HIF-1 α Gene Therapy 1.2 AdLacZ 2-month-old Limb Perfusion Ratio * ** 1.0 AdCA5 C57BL/6J mice Ad: 6x10 8 pfu 0.8 0.6 0.4 0.2 0.0 Pre Post 3 7 14 21 Time (days) M. Bosch-Marcé et al. Circ. Res. 2007;101:1310
Improved Recovery of Perfusion in Mice by HIF-1 α Gene Therapy 1.2 AdLacZ 2-month-old Limb Perfusion Ratio * ** 1.0 AdCA5 C57BL/6J mice Ad: 6x10 8 pfu 0.8 0.6 0.4 0.2 0.0 Pre Post 3 7 14 21 Time (days) 1.2 AdLacZ 1.0 Limb Perfusion Ratio AdCA5 0.8 ** 0.6 0.4 8-month-old 0.2 C57BL/6J mice Ad: 2x10 8 pfu 0.0 M. Bosch-Marcé et al. Pre Post 3 7 14 21 Circ. Res. 2007;101:1310 Time (days)
Improved Recovery of Perfusion in Mice by HIF-1 α Gene Therapy 1.2 AdLacZ 2-month-old Limb Perfusion Ratio * ** 1.0 AdCA5 C57BL/6J mice Ad: 6x10 8 pfu 0.8 0.6 0.4 0.2 AdCA5 gene therapy corrects age-related impairment of vascularization 0.0 Pre Post 3 7 14 21 Time (days) 1.2 AdLacZ 1.0 Limb Perfusion Ratio AdCA5 0.8 ** 0.6 0.4 8-month-old 0.2 C57BL/6J mice Ad: 2x10 8 pfu 0.0 M. Bosch-Marcé et al. Pre Post 3 7 14 21 Circ. Res. 2007;101:1310 Time (days)
HIF-1 Regulates the Expression of Angiogenic Growth Factors Hypoxia/Ischemia Increased HIF-1 Activity SDF1 SCF PLGF VEGF EPO ANGPT1 ANGPT2 PDGFB CXCR4 C-KIT VEGF-R1 VEGF-R2 EPOR TIE2 PDGF-R Mobilization and EPC Recruitment, Modulation of Recruitment of EC Proliferation/Survival, EC-SMC MSCs and BMDACs Activation Interactions Increased Tissue Vascularization
HIF-1 Regulates the Expression of Angiogenic Growth Factors Hypoxia/Ischemia Aging Increased HIF-1 Activity SDF1 SCF PLGF VEGF EPO ANGPT1 ANGPT2 PDGFB CXCR4 C-KIT VEGF-R1 VEGF-R2 EPOR TIE2 PDGF-R Mobilization and EPC Recruitment, Modulation of Recruitment of EC Proliferation/Survival, EC-SMC MSCs and BMDACs Activation Interactions Increased Tissue Vascularization
HIF-1 Regulates the Expression of Angiogenic Growth Factors Hypoxia/Ischemia Aging Increased HIF-1 Activity AdCA5 SDF1 SCF PLGF VEGF EPO ANGPT1 ANGPT2 PDGFB CXCR4 C-KIT VEGF-R1 VEGF-R2 EPOR TIE2 PDGF-R Mobilization and EPC Recruitment, Modulation of Recruitment of EC Proliferation/Survival, EC-SMC MSCs and BMDACs Activation Interactions Increased Tissue Vascularization
Control of Red Blood Cell Production Cardiovascular Disease Cancer
Advanced Human Cancers Commonly Contain Regions of Intratumoral Hypoxia Direct measurements of O 2 concentration in human tumors have demonstrated that P O 2 < 10 mm Hg is associated with a significantly increased risk of invasion, metastasis, and patient mortality. HIF-1 α expression by hypoxic cancer cells
HIF-1 α Overexpression is Associated with Patient Mortality
HIF Inhibitor Acriflavine Inhibits Tumor Growth and Vascularization in a Mouse Model of Prostate Cancer Acriflavine (ACF) inhibits dimerization of HIF- α and HIF-1 β subunits K. Lee et al. Proc. Natl. Acad. Sci. USA 2009;106:2353
HIF Inhibitor Digoxin Decreases Primary Tumor Growth and Metastasis in a Mouse Model of Breast Cancer Lung metastasis Lymph node metastasis Primary tumor growth Tumor cell area in axillary LN Saline Digoxin H. Zhang et al. Oncogene 2012;31:1757 L. Schito et al. Proc. Natl. Acad. Sci. USA 2012;109:E2707 C.C. Wong et al. J. Mol. Med. 2012;90:803
Treatment with Gemcitabine + HIF Inhibitor Digoxin Causes Tumor Eradication No treatment Tumor volume Gemcitabine Gemcitabine + Digoxin Days after injection of tumor cells D. Samanta et al. Proc. Natl. Acad. Sci. USA 2014;111:E5429
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