Visit our Expo - Redox and Inflammation signaling 2012

Hypoxia Signal Transduction in Health and Disease
Gregg L. Semenza
Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205 USA. Email:
gsemenza@jhmi.edu
In mammals, delivery of O 2 to cells is regulated by multiple homeostatic mechanisms, which
maintain a balance between O 2 supply and demand. O 2 concentrations must be tightly
regulated because of the risk of energy depletion or oxidative damage associated with
inadequate and excess O 2, respectively. Hypoxia-inducible factor 1 (HIF-1) is a master
transcriptional regulator of O 2 homeostasis. The half-life and transcriptional activity of the
HIF-1 subunit are controlled by O 2-dependent hydroxylation, which provides a
molecular mechanism for transducing changes in oxygenation into changes in gene
expression. HIF-1 controls the expression of genes whose protein products control O 2
delivery through the control of erythropoiesis (erythropoietin) and vascularization (vascular
endothelial growth factor, placental growth factor, stromal derived factor 1, platelet-derived
growth factor B, and angiopoietin-1and -2) growth. In addition to controlling the production
of cytokines that activate vascular endothelial cells, HIF-1 also controls cell-autonomous
responses of endothelial cells and bone marrow-derived progenitor cells. In preclinical
studies, administration of an adenovirus encoding a constitutively active form of HIF-
1 promotes both angiogenesis and arteriogenesis. A genetic polymorphism in the
human HIF1A gene is associated with absence of coronary collaterals in patients with
ischemic heart disease. HIF-1 overexpression is associated with increased risk of
mortality in many different human cancers and HIF-1 contributes to immortalization, genetic
instability, angiogenesis, glycolysis, autocrine growth factor signaling, invasion/metastasis,
and treatment failure. In the clear cell type of renal cell carcinoma, loss of function of the von
Hippel-Lindau tumor suppressor protein results in dysregulated HIF-1 activity that is
associated with the repression of E-cadherin gene expression, leading to the loss of cell-cell
adhesion that is required for invasion/metastasis. Several novel anti-cancer agents have antiangiogenic
effects that are related to their inhibition of HIF-1 activity. Thus, strategies
designed to inhibit or activate HIF-1 may represent a novel therapies in cancer and ischemic
cardiovascular disease, respectively, which are the major causes of mortality in industrialized
societies.
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