(Circulation. 2000;102:2255.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Angiogenesis Is Induced in a Rabbit Model of Hindlimb Ischemia by Naked DNA Encoding an HIF-1
/VP16 Hybrid Transcription Factor
From Genzyme Corp (K.A.V., Y.L., C.J., M.A.G., G.Y.A., R.J.G.) Framingham, Mass.; Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School (M.A.G.); and Department of Medicine and Biomedical Research, St Elizabeth’s Medical Center, Tufts Medical School (K.-G.S., M.M., R.A.T., J.M.I.), Boston, Mass. The first 2 authors contributed equally to this work.
Correspondence to Jeffrey M. Isner, MD, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail jisner{at}opal.tufts.com
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Abstract |
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Background—Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that regulates expression of genes involved in O2 homeostasis, including vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis. We sought to exploit this native adaptive response to hypoxia as a treatment for chronic ischemia.
Methods and Results—A hybrid protein consisting of DNA-binding
and dimerization domains from the HIF-1
subunit and the
transactivation domain from herpes simplex virus VP16 protein was
constructed to create a strong, constitutive transcriptional
activator. After transfection into HeLa, C6, and Hep3B
cells, this chimeric transcription factor was shown to activate
expression of the endogenous VEGF gene, as well as several
other HIF-1 target genes in vitro. The bioactivity of HIF-1/VP16
hybrid gene transfer in vivo was examined in a rabbit model of hindlimb
ischemia. Administration of HIF-1/VP16 was associated with
significant improvements in calf blood pressure ratio, angiographic
score, resting and maximal regional blood flow, and capillary density
(all P<0.01).
Conclusions—The HIF-1/VP16 hybrid transcription factor
is able to promote significant improvement in perfusion of an
ischemic limb. These results confirm the feasibility of a novel
approach for therapeutic angiogenesis in which neovascularization may
be achieved indirectly by use of a transcriptional regulatory strategy.
Key Words: transcription factors • ischemia • angiogenesis • collateral circulation • growth substances
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Introduction |
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Hypoxia-inducible factor-1 (HIF-1) was first identified as a factor critical for the inducible activity of the erythropoietin (EPO) 3' enhancer and is now recognized to be a key regulator of gene expression in response to changes in cellular oxygen tension.1 2 As a heterodimeric transcription factor, HIF-1 is composed of 2 basic helix-loop-helix (bHLH)–Per-ARNT-Sim (PAS) proteins, HIF-1
and HIF-1ß.3 The HIF-1 subunit is
an 826-amino-acid protein that is unique to HIF-1, whereas HIF-1ß is
the previously identified aryl hydrocarbon nuclear translocator (ARNT)
protein. The bHLH and PAS domains of HIF-1 and HIF-1ß comprise the
amino-terminal half of each protein and are required for DNA binding
and dimerization, whereas the transactivation domains are located
downstream.4 5 6 7 8 9 Two distinct transactivation domains have
been identified in HIF-1; one is located in the middle of the
protein (amino acids [aa] 530 to 580), and the other is found at the
extreme carboxyl-terminus (aa 780 to 826).6 7 9
Both HIF- and HIF-1ß mRNAs are expressed in most tissues of
humans, mouse, and rat.10 11 12 There is conflicting
evidence as to whether steady-state levels of HIF-1 mRNA may be
augmented slightly3 8 12 13 or not at
all10 11 13 14 in response to a hypoxic stimulus. However,
HIF-1 protein levels and HIF-1 DNA-binding activity both increase
markedly as cellular oxygen concentration is
reduced.3 14 15 When cells maintained at low oxygen
tension are returned to a nonhypoxic environment, HIF-1 protein
levels decay rapidly3 14 as the protein is degraded via
the ubiquitin-proteosome pathway.16 17 18 This observation
has suggested that stabilization of the HIF-1 protein is one
mechanism for hypoxic induction of HIF-1 protein expression and
consequently HIF-1 activity. The HIF-1 protein domain responsible
for hypoxia-dependent stabilization has been localized to the
central region of the protein between amino acids 400 and
600.9 17 19
We sought to exploit the adaptive response to hypoxia as an
alternative approach for the treatment of tissue ischemia.
Vascular endothelial growth factor (VEGF), an
endothelial cell–specific mitogen and potent
stimulator of angiogenesis,20 is a target of
HIF-1–mediated transcriptional activation.21 Previous
studies performed in animal models of peripheral and
myocardial ischemia have indicated that administration of VEGF
as a recombinant protein,22 23 as naked plasmid
DNA,24 25 or as a recombinant adenovirus26 27
may augment vascularity in ischemic tissues. Given these
findings, we considered that a modified HIF-1 transcription factor
administered via gene transfer might induce expression of VEGF and/or
downstream targets, ultimately leading to therapeutic
neovascularization of ischemic tissues.
Accordingly, we constructed a constitutively active form of HIF-1
consisting of the DNA-binding and dimerization domains from HIF-1
and the transactivation domain from herpes simplex virus VP16
protein.28 In vitro analyses of the HIF-1/VP16
hybrid transcription factor demonstrated that upregulation of
endogenous VEGF gene expression in HeLa and C6 cells as
well as both VEGF and EPO in Hep3B cells was independent of
hypoxia. Similar results were documented for other HIF-1 target
genes. Experiments were then performed in a rabbit hindlimb
ischemia model to test the hypothesis that transfection with
naked plasmid DNA29 encoding HIF-1/VP16 could enhance
collateral vessel development. Results of these studies suggest that
intramuscular injection of naked DNA encoding HIF-1/VP16 may
represent a viable treatment strategy for tissue
ischemia.
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Methods |
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Recombinant Plasmids
The full-length (aa 1 to 826) HIF-1
gene was isolated by
polymerase chain reaction (PCR) (Advantage cDNA PCR Kit, Clontech) from
a HeLa cell cDNA library (Clontech) and inserted between the
KpnI and XbaI sites of the expression vector,
pcDNA3 (Invitrogen). In this plasmid, gene expression is controlled by
the cytomegalovirus immediate early enhancer/promoter. The
HIF-1/VP-16 hybrid was constructed by truncating HIF-1 at aa 390
(an AflII site) and then joining the transactivation domain
of HSV VP-16 downstream. A VP16 fragment (aa 413 to 490) with
AflII and XbaI ends was amplified by PCR using
Vent polymerase (New England Biolabs), and this fragment was cloned
into the appropriate sites of the pcDNA3/HIF-1 construct. The
integrity of all sequences generated by PCR was verified by DNA
sequencing with an Applied Biosystems 377 DNA Sequencer. Restriction
enzymes and DNA-modifying enzymes were obtained from either New England
Biolabs or Life Technologies, Inc and used according to the
manufacturer’s specifications. Plasmid DNAs were purified with kits
obtained from Qiagen. The plasmid constructs
phVEGF165 and pCMVß have been described
previously.24
Transient Transfections
HeLa and C6 cells were grown in DMEM–high glucose (Irvine
Scientific) with 10% FBS (JRH Biosciences). Hep3B cells were
maintained in minimum essential (Eagle’s) medium supplemented with
Earle’s balanced salt solution and 10% FBS. For the analysis
of VEGF and EPO production, HeLa, Hep3B
(2x105 cells/well), and C6
(5x105 cells/well) cells were transfected in
triplicate in 6-well dishes with Lipofectamine (Life Technologies; 1
µg DNA and 4 µL Lipofectamine per well for HeLa and C6, 1 µg DNA
and 2.5 µL Lipofectamine per well for Hep3B cells) in Opti-MEM medium
(Life Technologies). The transfection was allowed to proceed for 16
hours. Five hours after the termination of transfection, 1 set of
dishes was maintained under normoxic conditions and 1 set was exposed
to hypoxia in a gas-controlled chamber (Espec) maintained at
1% O2, 94% N2, and 5%
CO2. The remaining set was treated with 100
mmol/L desferrioxamine. At 24 hours after induction, the culture medium
was harvested and the cells were lysed in 300 µL lysis buffer (0.5%
NP-40, 1 mmol/L EDTA, 50 mmol/L Tris [pH 8.0], 120
mmol/L NaCl, 100 mmol/L PMSF, 0.1 U/mL aprotinin, 1 mmol/L
Pefabloc, 5 mg/mL leupeptin). VEGF and EPO concentrations were assayed
by use of human VEGF– and EPO–specific ELISA kits (R&D Systems), and
the total cell protein was analyzed with the Bio-Rad protein
assay. ELISA values were normalized to total cell protein.
Protein Extraction and Immunoblotting
Hep3B cells were transfected as described above in duplicate
dishes (2.2x106 cells/100-mm dish). Twenty-four
hours after termination of the transfection, 1 set of dishes was
treated with 100 mmol/L desferrioxamine. Cells were harvested at
4, 8, and 24 hours after induction by lysis in 600 µL of lysis buffer
(see above). A total of 30 µg of protein was loaded onto Tris-glycine
polyacrylamide gels (6% for HIF-1 and 12% for
HIF-1/VP16). After transfer to PVDF membranes, the filters were
incubated with antibodies to HIF-1 (1:800; Novus Biologicals) or
VP16 (1:100; Santa Cruz) in 5% milk powder dissolved in TBST (10
mmol/L Tris-HCl [pH 8.0], 150 mmol/L NaCl, and 0.05% Tween 20).
The filter was developed with an enhanced chemiluminescence kit
(Amersham).
Isolation of RNA and Northern Blot Analysis
Total RNA was isolated from transfected HeLa cells with RNAzol B
(Tel-Test) according to the manufacturer’s instructions. Ten
micrograms of RNA was loaded in each lane of a 1% agarose–0.65%
formaldehyde gel. Probes (glycolytic enzymes, transferrin, the glucose
transporter Glut-1) were inserts isolated from cDNA clones obtained
from the ATCC; the HIF-1 probe was a
KpnI/AflII fragment from the pcDNA3HIF-1
plasmid; the ß-actin probe was generated by PCR from human genomic
DNA. The DNA fragments were 32P-labeled by
random-primer synthesis with a commercial kit (Stratagene).
Intramuscular Gene Transfer
Twenty-nine rabbits were used to study the effects of
intramuscular gene therapy on hindlimb ischemia. All protocols
were approved by St Elizabeth’s Institutional Animal Care and Use
Committee. Direct intramuscular gene transfer was performed in male New
Zealand White rabbits with hindlimb ischemia22 25
at 4 different sites in the ischemic limb to administer 500
µg of pHIF-1/VP16 (n=11), 500 µg of
phVEGF165 (n=10) as a positive control, or 500
µg of pCMVß (n=8) as a negative control. For each animal, 125 µg
in 0.5 mL of normal saline was injected at each of 4 sites. All outcome
analyses (see below) were performed by observers blinded to the
treatment regimen.
Red Blood Cell, Hematocrit, and Hemoglobin Measurements
Blood samples were drawn from the central artery of the rabbit
ear with a 23-gauge needle immediately before treatment (day 10) and on
the day rabbits were euthanized (day 40). Red blood cells, hematocrit,
and hemoglobin were measured by an automatic detector (Sysmex Alpha,
Sysmex Corp).
Calf Blood Pressure Ratio
Calf blood pressure was measured in both hindlimbs with a
Doppler flowmeter as described previously22
immediately before treatment (day 10) as well as 1 month after
initiation of the therapy (day 40). The calf blood pressure ratio was
defined for each rabbit as the ratio of the systolic pressure
of the ischemic limb to that of the normal limb.
In Vivo Doppler Flow Measurement
Blood flow was quantified in vivo before selective internal
iliac angiography on days 10 and 40 with a 0.018-in Doppler
guidewire (Cardiometrics) as previously described.25 The
Doppler-derived flow calculated in this fashion has been shown to
correlate with flow measurements determined by electromagnetic
flowmeters both in vitro and in vivo.25
Selective Angiography
Selective internal iliac angiography was performed as previously
described.22 Quantitative angiographic analysis of
collateral vessel development was performed with a grid overlay
composed of 2.5-mm-diameter circles arranged in rows spaced 5 mm
apart. The total number of grid intersections in the medial thigh area,
as well as the total number of intersections crossed by a
contrast-opacified artery, were counted in a single-blind fashion. An
angiographic score was calculated for each film as the ratio of grid
intersections crossed by opacified arteries divided by the total number
of grid intersections in the medial thigh.
Capillary Density
Tissue sections were stained for alkaline phosphatase with an
indoxyl-tetrazolium method to detect capillary
endothelial cells as previously
described30 and then were counterstained with
eosin. Twenty different fields from the 2 muscles were randomly
selected, and the numbers of capillaries and myofibers were counted to
determine capillary density (capillaries/mm2) and
the capillary-to-myocyte ratio.
Statistical Analysis
All results were expressed as mean±SEM. Statistical
significance was evaluated with an unpaired Student’s t
test for comparisons between 2 means and ANOVA followed by
Scheffé’s procedure for >2 means. A value of P<0.05
was considered to denote statistical significance.
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Results |
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Analysis of the HIF-1
/VP16 Hybrid In VitroA hybrid transcription factor, HIF-1
/VP16, composed of the
DNA-binding and dimerization domains from HIF-1 and the
transactivation domain from herpes simplex virus VP16 (Figure 1
) was constructed to provide strong,
constitutive activation of genes normally involved in the
physiological adaptation to hypoxia. As
predicted, in the HeLa, C6, and Hep3B cells transfected with the
HIF-1/VP-16 hybrid construct, production of VEGF was
significantly enhanced in cells maintained under normoxic conditions
(Figure 2, A, B, and C), indicating that
the HIF-1/VP16 hybrid is indeed constitutively active. VEGF levels
in HIF-1/VP16-transfected cells were increased 
10-fold over
normoxia-treated, mock-transfected HeLa cells, whereas a 3-fold
increase was observed in C6 and Hep3B cells. It is noteworthy that in
cells transfected with a plasmid expressing the full-length HIF-1
cDNA, VEGF levels were not enhanced over mock-transfected cells. This
result seems to conflict with those reported
previously5 31 ; however, those experiments used different,
potentially more sensitive measures of HIF-1 activity (eg,
activation of luciferase reporter constructs). The result described
here is not due to insufficient expression at the mRNA level, because
Northern analysis (Figure 4) shows that amounts of the
full-length HIF-1 and HIF-1/VP16 hybrid mRNAs are approximately
equivalent in the transfected cells.
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In cells under normoxic conditions, EPO levels were increased 300-fold
over similarly treated mock-transfected cells, and there was a 2- to
5-fold enhancement over cells subjected to hypoxia or treated
with DFO (Figure 2D
). Although hypoxia slightly augments
EPO expression in pHIF-1/VP16–transfected cells, we have
consistently observed a reduction with DFO treatment. A similar
effect has been documented previously32 33 ; in those
experiments, EPO expression in Hep3B cells cotreated with
hypoxia and DFO was less than that in cells treated with
hypoxia alone. This effect was not observed with VEGF, because
VEGF expression in HIF-1/VP16-transfected cells was enhanced by DFO
in all 3 cell lines examined (Figure 2, A, B, and C).
Western analysis (Figure 3)
showed that the HIF-1/VP16 hybrid accumulates to an equal extent
under normoxic conditions and after induction with DFO; these levels
persist during the 24 hours of incubation with DFO (Figure 3).
In contrast, as previously documented,3 14 15 the
full-length HIF-1 protein is unstable with normoxia. DFO treatment
results in an increase in the level of HIF-1 protein at all time
points examined. In this experiment, the lack of detectable
endogenous HIF-1 in the mock-transfected cells may be
attributable to the time point at which the analysis was
performed (24 hours); a previous study3 of HIF-1
protein levels in Hep3B cells had demonstrated a peak at 4 to 8 hours
of hypoxia with reduced levels after 16 hours of treatment.
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As shown in Figure 4, the HIF-1/VP16
hybrid also activated expression of lactate dehydrogenase
A, phosphoglycerate kinase 1, enolase 1, aldolase A, and the
Glut-1 and transferrin genes under normoxic conditions. The
Northern blot analysis data confirm that the effect of
HIF-1/VP16 on VEGF induction is more potent than that achieved by
hypoxia.
In Vivo Red Blood Cell Measurements
Expression of naked plasmid DNA encoding either the HIF-1/VP16
hybrid (pHIF-1/VP16) or human VEGF165
(phVEGF165) was analyzed by reverse
transcription–PCR and found to persist to 14 days after administration
(data not shown). There was no difference in red blood cell count
(520±5 to 539±15x104/mL) or hemoglobin
(11.3±0.1 to 11.9±0.1 g/dL) for phVEGF165,
pHIF-1/VP16, and control groups before or after treatment. Although
the hematocrit appeared to increase in pHIF-1/VP16–treated animals
(0.327±0.001 to 0.365±0.013), a similar increase was observed in
controls (0.331±0.010 to 0.363±0.006), suggesting that this result
was not due to expression of the HIF-1/VP16 hybrid transcription
factor.
Analysis of Blood Pressure and Flow
The blood pressure ratio at day 40 was significantly higher in the
pHIF-1/VP16–treated animals (0.93±0.02) (P<0.01) than
in the phVEGF165 (0.82±0.03) or pCMVß
(0.69±0.02) treatment groups (Figure 5A).
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At day 40, the resting and papaverine-stimulated maximal blood flows in
the pHIF-1/VP16–transfected (41.6±3.1 and 111.2±5.7 mL/min,
respectively) and phVEGF165-transfected
(42.2±3.9 and 88.7±7.4 mL/min) groups were significantly higher than
that of the pCMVß group (28.7±1.5 and 65.3±3.8 mL/min) (Figure 5, B and C). The resting flow was similar between
pHIF-1/VP16– and phVEGF165-treated rabbits at
day 40; however, the maximal flow was significantly higher
(P<0.05) in the animals transfected with pHIF-1/VP16
than in the phVEGF165-treated group.
Analysis of Collateral Vessel Development
By day 40, angiographic scores in the pHIF-1/VP16–treated
(0.61±0.01) and phVEGF165-treated (0.58±0.03)
rabbits were significantly higher (P<0.01 and
P<0.05, respectively) than that of the negative control
group (0.51±0.05) (Figures 5D and 6). There was no statistically
significant difference in angiographic score at 40 days between the
pHIF-1/VP16–treated and phVEGF165-treated
groups.
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Capillary densities observed in the muscles of the
pHIF-1/VP16-treated group (255±13/mm2) and
the phVEGF165-treated group
(210±10/mm2) were significantly higher
(P<0.01) than that of the pCMVß-treated group
(150±4/mm2) (Figure 5E). In addition, the
capillary density was higher (P<0.05) in the animals
transfected with pHIF/VP16 than in the
phVEGF165-treated animals. Moreover, the
capillary/muscle fiber ratios of the pHIF-1/VP16– and
phVEGF165-transfected rabbits (0.88±0.06 and
0.75±0.03, respectively) were significantly higher
(P<0.05) than that of the negative control (0.58±0.03).
Light-microscopic evidence of frank myonecrosis was not observed in any
of the groups.
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Discussion |
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Hypoxic induction of gene expression is thought to involve the interaction of multiple transcription factors at the promoter. HIF-1 is known to interact with other DNA-binding transcription factors such as HNF-4; cooperation with this factor is thought to allow high-level and tissue-specific expression of the EPO gene.34 Activation of EPO gene expression in response to hypoxia also depends on interaction of HIF-1 with p300, a global transcriptional coactivator.34 35 In addition, hypoxic induction of the LDH-A gene has been shown to involve a multiprotein complex composed of HIF-1, CREB-1/ATF-1, and p300.36 Transcriptional activation of VEGF and the other HIF-1 target genes by the HIF-1
/VP16 hybrid factor in vitro and in vivo suggests that
HIF-1/VP16 is able to interact with the accessory factors required
for expression of these genes in the cell types examined (human
cervical epithelia, human hepatoma, rat glioma, rabbit skeletal
muscle).
Anatomic evidence of revascularization in response
to administration of pHIF-1/VP16 was observed at 2 levels. First,
histological examination documented an increase in
vascularity at the capillary level that exceeded the negative control
for both pHIF-1/VP16 and phVEGF165; the
observed increase was greater in the HIF-1/VP16–treated animals
than in those that received phVEGF165. This
increased capillary vascularity most likely contributed to the higher
level of maximal blood flow in animals that received pHIF-1/VP16
compared with the phVEGF165-treated group.
Second, systematic quantification of angiographic recordings
established that the number of angiographically visible collateral
arteries in the HIF-1/VP16–treated animals was similar to that
achieved with phVEGF165, and both exceeded that
of the negative control.
No change in red blood cell count, hematocrit, or hemoglobin was
observed before or after intramuscular administration of HIF-1/VP16.
This result implies that EPO gene expression (normally limited to the
fetal liver and adult kidney) was not activated, as expected if
transgene expression was limited to the site of administration. This
result also implies that the HIF-1/VP16 hybrid factor does not
circumvent the regulatory mechanisms maintaining tissue specificity of
EPO gene expression.
Certain features of HIF-1/VP16 make it an attractive candidate for
strategies of therapeutic angiogenesis. First, it is possible that
after administration of HIF-1/VP16, expression of all isoforms of
VEGF-1 may be augmented, quantitatively or qualitatively exceeding the
angiogenic effect achieved by gene transfer of a single isoform.
Second, in addition to VEGF, HIF-1/VP16 may activate
expression of additional genes that promote angiogenesis. It has been
reported that hypoxic induction of expression of Flt-1, 1 of 2 VEGF
receptors, is mediated by a HIF-1 binding site found upstream of the
gene.37 HIF-1 may also upregulate expression of the
urokinase receptor to enhance cellular migration and
invasion.38 Furthermore, there may be additional, as yet
uncharacterized factors involved in angiogenesis that are regulated by
HIF-1 and therefore possibly activated by HIF-1/VP16.
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Acknowledgments |
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This work was supported in part by a research fellowship from Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan (K.-G.S.), and by a research fellowship from the Interuniversity Cardiology Institute of the Netherlands (R.T.). The authors thank David Souza for sequencing the HIF-1
cDNA and Hsienwie
Lu for technical assistance. We acknowledge Gregg Semenza for
helpful discussions. Received June 1, 2000; revision received June 5, 2000; accepted June 5, 2000.
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