Abstract
Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO) mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX), exposed for two weeks to normobaric chronic hypoxia (CH) or two weeks of CH followed by two weeks of normoxic recovery (REC). Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off), 230 genes were identified and separated into four distinct temporal categories. Class I) contained 1 transcript up-regulated in both CH and REC; Class II) contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III) contained 9 transcripts down-regulated both in CH and REC; Class IV) contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1) by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia.
Highlights
Since the pioneering studies of Paul Bert, Denis Jourdanet and Francois-Gilbert Viault conducted in late 1800, it is well known that hypoxia, due to reduced oxygen tension noted at high altitude, is a primary physiological stimulus for erythrocyte production in both animals and humans [1,2]
Expression Profile To identify and define gene expression changes that occur in peripheral blood during hypoxia and normoxic recovery, expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice
Our goal in this study was to identify the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia to identify novel genes to be used as possible reference genes detectable by quantitative polymerase chain reaction (qPCR) in small samples of peripheral blood
Summary
Since the pioneering studies of Paul Bert, Denis Jourdanet and Francois-Gilbert Viault conducted in late 1800, it is well known that hypoxia, due to reduced oxygen tension noted at high altitude, is a primary physiological stimulus for erythrocyte production in both animals and humans [1,2]. In the 20th century, Carnot and De Flandre suggested the existence of a humoral agent that responds to hypoxia and induces erythropoiesis [3]. Several experiments demonstrated that plasma contains the humoral agent erythropoietin (EPO) capable of inducing hematopoiesis during hypoxic and anemic conditions [4]. EPO acts synergistically with granulocyte-macrophage colony-stimulating factor, stem cell factor, and interleukins 3, 4 and 9 as well as insulin growth factor-1 in the later stages of erythropoiesis. Along with EPO, other cytokines and growth factors induce proliferation, maturation and survival first in the burst forming unit-erythroid and in the colony forming uniterythroid. The final result is an increase of reticulocytes which can be measured in the peripheral blood stream, and an increase in the number of mature erythrocytes and hematocrit [6]
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