Transcript Oxygen Sensing, Homeostasis, and Disease NEJM. August 2011

OXYGEN SENSING, HOMEOSTASIS,
AND DISEASE
SEMENZA.NEJM, AUGUST 2011, 246: 6
Amelia Crawford PA-S2
Hypoxia Inducible Factor 1
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All nucleated cells in the human body respond
to hypoxia
HIF-1 plays a critical role in the cells’ response.
When oxygen availability is decreased, HIF-1
regulates the expression of genes that mediate
adaptive responses by cells
Hypoxia Inducible Factor 1
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HIF-1 is composed of a beta and an alpha subunit.
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The alpha subunit is oxygen regulated
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In aerobic conditions, HLF-1 (alpha) is normally hydroxylated and
then degraded by proteasomes
In hypoxic conditions, the hydroxylation is inhibited, HIF-1 (alpha)
accumulates, and it up regulates several genes to promote survival in
cells
Stimulates erythropoetin, angiogenesis, & glycolytic metabolism
HIF-1
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HIF-1 and Cardiovascular Disease
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Atherosclerotic disease causes stenosis of vessels and results in
decreased blood flow distally.
Decreased blood flow →decreased O2 supply
In studies with mice in which the femoral artery was ligated,
induction of HIF-1 resulted in increased activation of VEGF, which
eventually caused angiogenesis and reperfusion of the limb via the
production of collateral blood flow.
The normal adaptive vascular response is impaired by aging &
DM—major causes of CAD and PVD
HIF-1 and Cardiovascular Disease
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VEGF other factors promote angiogenesis by stimulating vascular cells
and also by mobilizing bone-marrow derived angiogenic cells (BMDACs)
BMDACs = myeloid cells that stimulate vascular remodeling.
In order to initiate a vascular response, they must mobilized from bone
marrow, enter the peripheral blood, and be retained within the ischemic
tissue by adhering to the vascular endothelium.
Aging results in the loss of ischemia induced expression of angiogenic
factors and BMDAC mobilization and consequently, angiogenesis and
reperfusion are decreased.
HIF-1 and Cardiovascular Disease
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HIF-1α induction occurs early in the course of a MI
In studies with mice with an over expression of HIF-1α that underwent
coronary artery ligation, there was a smaller infarct size, improved cardiac
function, and increased capillary density.
Collateral vessels are routinely identified in 2/3 of patients with critical
coronary artery disease that is sufficient to cause angina.
Patients with a collateral blood supply that eventually suffered a MI also had
smaller infarcts and were more likely to survive than those without a
collateral vessels.
HIF-1 also helps the heart to survive episodes of O2 deprivation by inducing
glycolytic metabolism & adenosine production
HIF-1 and Cardiovascular Disease
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Pharmacologic agents that activate HIF-1 are a therapeutic target in
treating patients with CAD and PVD (Gene therapy)
In preclinical trials, patients with CAD or PVD were given a
recombinant adenovirus that encoded for a protein that contained the
terminal half of HIF-1 alpha gene fused to an activator protein.
It was administered either via an IM injection (PVD) or intramyocardial
injections (CAD) prior to CABG
No adverse effects were seen but also no reports of efficacy were
released. This could be due to the fact that the protein did not contain
all of the HIF-1 alpha gene and in turn did not encode for all the
activities of the gene.
HIF-1 and Cardiovascular Disease
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Another pharmacologic alternative for targeting
HIF-1 in cardiovascular disease is the development
of drugs that inhibit the hydroxylation of HIF-1.
These drugs either:
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chelate Fe, (Fe is present in the center of the
hydroxylases) or
 2. compete with the hydroxylases at the binding site
HIF-1 and Cardiovascular Disease
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A final alternative would be the use of HIF target gene
products as therapeutic agents.
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Already been done via cloning of erythropoietin gene and
production of recombinant human erythropoietin.
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Used in chronic renal failure patients to stimulate RBC production
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However administration of a single angiogenic factor such as VEGF
fails to stimulate a vascular response.
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Benefit of using downstream proteins as therapeutic agents is that
they act immediately whereas gene therapy requires more time for
trascription and translation of target gene products.
HIF-1 and Cancer
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In cancer the physiologic responses to hypoxia aids
in disease progression
Tumor vessels are structurally & functionally
abnormal and contain areas of severe hypoxia.
This results in HIF-1 over expression, which causes
additional angiogenesis, genetic instability, immune
evasion, metabolic reprogramming, and invasion,
and metastasis.
HIF-1 and Cancer
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Hypoxia within the tumor is a major mechanism that
activates HIF-1
Loss of tumor suppressor function or increased
oncogene function also activates HIF-1.
HIF-1 regulates a myriad of target genes
However, only a small subset of genes in any given
cancer will be regulated by HIF-1
The role of HIF-1 in a specific cancer can guide
possible therapies.
HIF-1 and Cancer
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A number of chemotherapy agents are directed at
inhibiting HIF-1
 Topotecan
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Also cardiac glycosides like Digoxin have been
shown to decrease HIF-1 and subsequent tumor
growth in mice.
Others are agents aimed at blocking HIF-1 are
being investigated
HIF-1 and Pulmonary Hypertension
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Pulmonary hypertension is a progressive and often
fatal consequence of chronic lung disease
In contrast to systemic arterioles which dilate in
order to increase tissue perfusion during hypoxia,
pulmonary arterioles constrict to shunt blood away
from areas of the lung that are not ventilated
This eventually leads to cor pulmonale and
progressive hypoxemia.
HIF-1 and Pulmonary Hypertension
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HIFs regulate target genes that play major roles in
the pathology of pulmonary HTN.
 Alveolar
hypoxia induces HIF-1 activity in vascular
smooth muscle cells and alters the intracellular
concentrations of K, Ca, & H ions
 This leads to smooth muscle cell hypertrophy,
proliferation, depolarization, & contraction and
increased pulmonary vascular resistance
HIF-1 and Pulmonary Hypertension
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Tibetans live in conditions of chronic hypoxia & they
have blunted responses to hypoxia, which prevents the
development of pulmonary hypertension.
Gene sequencing has revealed loci encoding HIF-2α,
hyroxylases (PHD2), factor inhibiting HIF-1, and HIF
target genes as playing a significant role in the
adaptation that Tibetans exhibit.
 Alters
vascular, erythropoeitic, and metabolic responses to
hypoxia
Conclusions
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HIF-1 is an adaptive response in cardiovascular and
peripheral vascular disease
HIF-1 is mal-adaptive in cancer
HIF-1 is also maladaptive in chronic lung disease
and pulmonary hypertension.
The targeting of HIFs and its inhibitors and
activators offer possible treatment options of these
diseases.