Published online before print March 30, 2001, doi: 10.1161/hh0701.088842
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© 2001 American Heart Association, Inc.
Integrative Physiology |
Ischemic Preconditioning Upregulates Vascular Endothelial Growth Factor mRNA Expression and Neovascularization via Nuclear Translocation of Protein Kinase C 
in the Rat Ischemic Myocardium
From the First Department of Internal Medicine (H. Kawata, A.K., H. Kurioka, E.T., Y.S., T.H., K.D.), Nara Medical University, Nara; Department of Forensic Medicine (K.-i.Y., K.H., M.K.), Graduate School of Medicine, University of Tokyo; and Department of Anatomy and Cell Biology (T.U.), Wakayama Medical College, Wakayama, Japan.
Correspondence to Ken-ichi Yoshida, MD, Department of Forensic Medicine, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail kyoshida{at}m-u.tokyo.ac.jp
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Abstract |
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Abstract—Ischemic preconditioning (IP) exerts cardioprotection through protein kinase C (PKC) activation, whereas myocardial ischemia enhances vascular endothelial growth factor (VEGF) mRNA expression. However, the IP effect or the involvement of PKC on the VEGF expression is unknown in myocardial infarction. We investigated whether IP enhances VEGF gene expression and angiogenesis through PKC activation in the in vivo myocardial infarction model. Sprague-Dawley rats were assigned into the following 3 groups: the sham group; the IP group, which underwent 3 cycles of 3 minutes of ischemia and 5 minutes of reperfusion (IP procedure); and the non-IP group. The latter 2 groups were subsequently subjected to left anterior descending coronary artery occlusion. To examine the involvement of PKC, the PKC inhibitor chelerythrine (5 mg/kg) or bisindolylmaleimide (1 mg/kg) was injected intravenously before the IP procedures. PKC
was translocated to the nucleus after
10 minutes of ischemia after the IP procedure but was not
translocated in the non-IP and the sham groups. VEGF mRNA expression 3
hours after infarction was significantly higher in the IP group than in
the non-IP and the sham groups. Capillary density in the infarction was
significantly higher, whereas the infarct size was smaller in the IP
group than in the non-IP group at 3 days of infarction. Chelerythrine
but not bisindolylmaleimide blocked all of the IP effects on the
nuclear translocation of PKC, enhancement of VEGF mRNA expression
and angiogenesis, and infarct size limitation. These results
show that IP may enhance VEGF gene expression and angiogenesis through
nuclear translocation of PKC in the infarcted
myocardium.
Key Words: angiogenesis • ischemic preconditioning • myocardial infarction • protein kinase C • vascular endothelial growth factor
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Neovascularization is induced both under physiological conditions such as wound healing and maturation of ovarian follicles and under pathological conditions including tumor, rheumatoid arthritis, and retinopathies.1 2 Neovascularization also plays a pivotal role in the remodeling of cardiac tissue after ischemia and infarction.3 4
Vascular endothelial growth factor (VEGF), an angiogenic mitogen, is a highly specific growth factor for vascular endothelial cells both in vitro and in vivo.5 6 VEGF mRNA is induced by hypoxia in cultured cells.7 8 Previous studies showed that transient ischemia upregulates VEGF mRNA in cardiac tissues, suggesting that VEGF mediates neovascularization during myocardial ischemia.8 9
It is well known that repetitive transient
ischemia-reperfusion confers the protective effect, referred to
as ischemic preconditioning (IP), on the myocardium
against subsequent prolonged
ischemia.10 11 12
The protection resulting from IP is manifested as a reduction in
infarct size, decreased incidence of arrhythmias, and improved
postischemic contractile
dysfunction.12 13
Many studies showed that the effects of IP are mediated by protein
kinase C
(PKC).11 12 14
Among >10 PKC isoforms, we showed that PKC
, -
, -, and -
isoforms are expressed in rat
myocardium.15 16
We showed that either PKC or PKC is required for the protective
effect of IP in the isolated rat
heart.17 18 More
recent studies indicated that the PKC isoform especially plays a
pivotal role in the cardioprotection conferred by
IP.14 19 Although
PKC activation is important in IP, the role of each PKC isoform has not
been fully elucidated except for the link between PKC and
ecto-5'-nucleotidase.12 20
Although implications for the effect of IP were not sought, a
recent paper shows the binding of PKC to 36 proteins such as
signaling molecules, structural proteins, and stress-activated
proteins in the
heart.21
The activation of PKC also plays a key role in the
intracellular signaling pathway for cellular
growth.22 It has been shown
that PKC is involved in the growth of endothelial cells
during angiogenesis23 and
that VEGF requires PKC activation for its angiogenic
effect.24 25 On
the other hand, hypoxia-inducible factor-1 (HIF-1), a
transcription factor, is induced by hypoxia and
activates genes related to angiogenesis including VEGF,
erythropoietin, and
endothelin-1.26 27
Previous study showed that HIF-1 is induced transiently in the
ischemic or infarcted myocardium, followed by
upregulation of the VEGF
gene.28 However, it is not
known in the heart whether PKC or HIF-1 lies upstream of the
signaling pathway of the VEGF-mediated angiogenesis both in vivo and in
vitro.
Our clinical studies showed that the serum levels of VEGF were significantly higher in patients with acute myocardial infarction (AMI) than in those without29 and that the level was higher in the AMI patients with preinfarction angina than in those without.30 These findings led us to hypothesize that IP increases VEGF level through PKC activation, thereby increasing capillary density through the induction of the VEGF gene in the course of AMI. In this study, we sought to test this hypothesis in the rat model of AMI.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials
Male Sprague-Dawley rats age 8 weeks (n=239) (SLC Japan, Shizuoka, Japan) were anesthetized with sodium pentobarbital (50 mg/kg, IP). The experimental protocol was approved by the University of Tokyo and Nara Medical University committees on animal experiments.
Surgical Procedure
The left anterior descending coronary artery
(LAD) was ligated as previously
described.9 In the IP group,
the ligature was released for 5 minutes after LAD ligation for 3
minutes (3-minute ischemia and 5-minute reperfusion), and after
3 cycles of this procedure (IP procedure), the LAD was reoccluded to
induce infarction. In the non-IP group, the rats underwent the LAD
ligation for infarction after a 24-minute nonischemic period
without the IP procedure. The rats in the sham group underwent the same
procedure except for the LAD ligation.
PKC Isoform Distribution
To localize PKC isoforms in the ischemic
area, 10 minutes after the surgical procedures, Western blotting of the
subcellular fractions (n=5) and immunohistochemical staining of the
frozen sections (n=3) were performed as previously described by use of
antibodies to PKC, -, -, and - (Transduction
Laboratories).15 17 18 31 32 33 34 35
VEGF mRNA Expression
Northern hybridization was performed as previously
described9 36 to
measure the VEGF mRNA levels in the infarcted and the
nonischemic tissues after 3 hours of infarction after the IP or
the non-IP procedure (n=5) and to evaluate the temporal change in the
infarcted areas 3, 6, and 12 hours and 1, 2, 3, and 7 days after
infarction (n=3). The primers for VEGF were the following: sense,
5'-CCGAATTCATGAACTTTCTGCT-3', and antisense,
5'-GAGGAAGCTTCTTCCTGCCAGC-3'. The signals of specific mRNAs were
quantified by use of a bio-imaging analyzer (BAS 5000, Fujix)
and were normalized by GAPDH mRNA
signals.9 The VEGF mRNA
levels in each cardiac tissue sample from the IP and the non-IP groups
were expressed as percentage of the mean value of the sham group
(100%). In situ hybridization was also performed on the
horizontal sections of the heart sampled 3 hours after infarction (n=3)
as we previously
described.37 The probes for
VEGF were the following: antisense,
5'-ATCTCTCCTATGTGCTGGCTTTGGTGAGGTTTGATCCGCA-3',
and sense,
5'-TGCGGATCAAACCTCACCAAAGCCAGCACATAGGAGAGAT-3'.
HIF-1 Expression
Western blotting of the subcellular fractions from
the ischemic tissues after 0.5, 1, and 2 hours of
ischemia after the IP or non-IP procedure (n=3) was performed
as previously described by use of antibody to HIF-1 (Santa Cruz
Biotechnology).15 17 18 31 32 33 34 35 38
Capillary Density
Immunostaining by use of anti-rat
CD31 antibody (PharMingen) was performed as previously
described39 to determine the
capillary density in the infarcted areas 1 or 3 days after infarction
(n=3). We examined the capillary density in the whole infarcted area on
the 3 horizontal sections between the point of ligation and the apex
under microscopy. The capillaries were recognized as tubular structures
positively stained for CD31.
Infarct Size
Infarct size and area at risk 3 days after infarction
(n=5) were measured as previously
described.4 40 The
infarct size was measured in the 8 horizontal sections between the
point of ligation and the apex. The area at risk was recognized as the
area demarcated with 0.3% Evans blue dye, whereas the noninfarcted
(stained) and infarcted (not stained) areas were determined after
incubation with 1% triphenyltetrazolium
chloride (Sigma).
PKC Inhibitor Study
Previous studies showed that chelerythrine abolished
the myocardial protection initiated by
IP11 and inhibited the
activation of PKC in the heart induced by IP in the isolated
heart17 18 and in
vivo (5 mg/kg).14 On the
other hand, another PKC-specific inhibitor,
bisindolylmaleimide, neither inhibited the translocation of PKC (but
did inhibit PKC and -) in the isolated rat
heart18 nor suppressed the
cardioprotection by IP in the isolated
heart18 or in
vivo.41 The rats were
injected intravenously with chelerythrine (5 mg/kg),
bisindolylmaleimide (1 mg/kg) (Sigma), or vehicle (0.5 mL/kg,
50% DMSO in physiological saline) just before the
IP procedure before LAD ligation (n=90). The sham rats (n=13) received
the vehicle and underwent the surgical procedure except for LAD
occlusion. Parameters for the IP effects were determined as
described above. All of the measurements were performed with the
observers being blinded to grouping.
Statistical Analysis
Data are presented as mean±SD. Significance
(P
0.05) was determined by
ANOVA followed by post hoc analysis with the Fisher
procedure.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PKC Isoform Distribution
Figure 1A
shows representative blots
indicating the distribution of PKC isoforms in the
myocardium rendered ischemic for 10 minutes after
the surgical procedure.
Figure 1B shows the quantitative data from the blots. The
PKC level in the P1 (nucleus-myofibril) fraction was
significantly higher in the IP group than in the non-IP and sham
groups, whereas the levels of PKC, -, and - in the P1 fraction
were similar among the 3 groups. IP redistributed PKC from the
cytosol fraction (S in the figure) to the P1 fraction, whereas there
was no translocation to the P2 (membrane) fraction in the all groups.
Almost all of the PKC was distributed to the extract but not to the
residue after Triton X-100 treatment of the P1 fraction (data not
shown). We previously reported that the Triton X-100 extract and
residue represent the nuclear fraction and the myofibril
fraction,
respectively.32 42
The difference in the translocation of PKC between the IP and the
non-IP groups was not detected immediately after the IP procedure but
was evident after 10 minutes of ischemia subsequent to the IP
procedure and thereafter (data not shown). Immunohistochemical staining
confirmed the nuclear translocation of PKC in the myocardial cells
after IP and ischemia
(Figure 1C). These results show that IP and ischemia
induces specific translocation of PKC from the cytosol to the
nucleus in the myocardium.
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IP Upregulates VEGF mRNA
The VEGF mRNA migrated primarily as a 3.9-kb band
(Figure 2A) on the Northern blot, as reported
previously.7 9 The
VEGF mRNA was upregulated in the infarcted but not in the noninfarcted
area after 3 hours of LAD occlusion after the IP but not the non-IP
procedure
(Figures 2A and 2B). In situ hybridization revealed that VEGF
mRNA is upregulated in the infarcted but not in the noninfarcted
cardiomyocytes only after the IP procedure, although VEGF
mRNA is expressed predominantly in the vascular
endothelial cells in the noninfarcted area in all of
the groups as well as in the infarcted area without the IP procedure
(Figure 2C).
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Figures 2D
and 2E show the chronological change of VEGF mRNA
expression in the infarcted area. In the IP group, the VEGF mRNA level
was rapidly elevated with a peak at 3 hours after infarction, with a
significantly higher level at 3 to 12 hours in the IP group than that
in the non-IP group. In the non-IP group, VEGF mRNA was more slowly but
significantly upregulated, with a peak level at 2 days but without
difference between the IP and the non-IP groups at 1 to 3 days after
infarction. The maximum levels of the VEGF mRNA expression were
2-fold higher in the IP group than in the non-IP group. These
results suggest that IP upregulates VEGF mRNA expression in the
infarcted cardiomyocytes in the early phase of
AMI.
Expression of HIF-1
HIF-1 was similarly induced in the P1
(Figure 3) but not in the cytosol (not shown) fraction of the
ischemic heart at all time points examined as compared with the
sham heart. There was no difference between the IP and the non-IP
groups, suggesting that IP upregulates VEGF gene independently of the
HIF-1 induction.
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IP Increases Capillary Density in the
Infarcted Area
We evaluated the capillary density in the infarcted
area 1 and 3 days after infarction that followed the IP or the non-IP
procedure on the basis of the previous studies showing that capillary
growth is induced significantly at 24 to 72 hours after stimulation
with growth
factors.4 43
Figure 4A shows the representative
appearances in the immunohistochemical staining of CD31 in the
infarcted myocardium of the IP and the non-IP groups. IP
enhanced the neovascularization similarly in the periphery (shown in
Figure 4A) and in the core (not shown) of the infarction
after 3 days of LAD occlusion. The capillary density in the infarcted
area was significantly higher in the IP group 3 days after infarction
than in the non-IP groups 1 and 3 days, as well as in the IP group 1
day, after infarction
(Figure 4B). In further support of neovascularization, there
was increased blood flow because anti-albumin
immunostaining showed an increased number of tubular
structures (data not shown).
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IP Reduces Infarct Size
As shown in
Figure 4C, IP significantly reduced infarct size, ie, the
ratio of infarcted area to left ventricle area (16.2±4.3% in the IP
group versus 23.8±1.4% in the non-IP group; 32% reduction,
P<0.01) and the ratio of
infarcted area to area at risk (41.1±5.2% in the IP group versus
52.8±6.2% in the non-IP group; 22% reduction,
P<0.05). IP also reduced the
ratio of area at risk to left ventricle area, although not
significantly (38.0±5.8% in the IP group versus 46.3±5.0% in the
non-IP group).
PKC Inhibitor Suppresses IP
Effects
In the vehicle and bisindolylmaleimide groups,
PKC translocated from the cytosol fraction to the P1 fraction in the
heart rendered ischemic for 10 minutes after the IP procedure,
whereas in the chelerythrine and sham groups, the translocation of
PKC was not detected. In all of the groups, there was no significant
translocation of PKC, -, and -. Thus, the translocation of
PKC induced by IP was inhibited by chelerythrine but not by
bisindolylmaleimide
(Figures 5A and 5B).
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Consistent with the data on PKC
translocation, VEGF mRNA upregulation after 3 hours
(Figure 6) and angiogenesis
(Figures 7A and 7B) and infarct size limitation
(Figure 7C) after 3 days of infarction after IP were
inhibited by chelerythrine but not by bisindolylmaleimide.
Additionally, HIF-1 is not considered to be involved in the effect
of IP on VEGF mRNA induction because chelerythrine did not inhibit the
HIF-1 induction in the myocardium infarcted for 0.5 to 2
hours after the IP procedure
(Figure 8).
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Taken together, these data show that the PKC
inhibitor chelerythrine inhibited the effects of IP on the
activation of PKC, the induction of VEGF mRNA, the enhancement of
angiogenesis in the infarcted myocardium, and the reduction
of the infarct size. Therefore, it is likely that IP translocates
PKC to the nucleus, thereby upregulating VEGF mRNA and the capillary
angiogenesis in the infarcted myocardium, resulting in
myocardial protection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The major findings of the present study are that IP induced translocation of PKC
isoform to the nucleus and enhanced
expression of VEGF mRNA in the infarcted cardiac myocytes, thereby
inducing capillary angiogenesis and reducing the infarct size in the in
vivo model of rat AMI. Chelerythrine, a selective PKC
inhibitor, inhibited all of the effects of IP, supporting
the close association between PKC activation, VEGF mRNA upregulation,
enhanced angiogenesis, and the infarct size limitation conferred by
IP.
Previously, we showed that PKC or - exerts the
protective effect of IP through membrane translocation in the isolated
rat heart.18 Recent studies
also showed that PKC is a key effector in cardiac protection
initiated by IP in cultured rat cardiac myocytes and conscious
rabbits.14 19
Consistent with these studies, the present study
demonstrated for the first time that IP translocates PKC to the
nucleus in the in vivo model of myocardial infarction in the rat heart.
There are many proposed substrates for PKC in the membrane, such as
ATP-sensitive potassium (KATP) channel,
1 adrenoceptor, adenosine receptor,
and
ecto–5'-nucleotidase.12 20 44 45 46
Therefore, the membrane translocation of PKC has been thought to be a
fundamental process in the protection conferred by IP at least in the
early phase. By contrast, another fundamental finding of this study is
that the nuclear translocation of PKC and the upregulation of a gene is
involved in the late phase of IP. Consistent with our findings,
Ping et al21 recently showed
that PKC lies in the nuclear and mitochondrial compartments with
physical association with many functional proteins.
Hypoxia is a strong inducer of VEGF.7 8 Recent studies showed that transient ischemia or hypoxia enhances the expression of VEGF mRNA and that VEGF induces angiogenesis in the ischemic or infarcted heart.8 9 Consistent with these findings, the present study showed that IP enhanced the expression of VEGF mRNA in the ischemic cardiac myocytes in addition to vascular endothelial cells, as denoted by in situ hybridization. Furthermore, we found that the capillary density in the infarcted area increased, whereas the infarct size was reduced significantly at 3 days after the onset of AMI preceded by IP, and this neocapillarization and cardioprotection followed the enhanced expression of VEGF mRNA. Consistent with the protective effect of VEGF on ischemic myocardium, Luo et al47 reported that addition of VEGF to the hyperkalemic cardioplegic solution protected the heart functionally against ischemia-reperfusion injury in the isolated rat heart. Additionally, several lines of evidence support the idea that VEGF contributes to cardioprotection through the induction of angiogenesis.3 4 Taken together, it is likely that IP exerts its cardioprotective effect at least in some portion through the angiogenesis induced by VEGF.
HIF-1 is involved in the upregulation of VEGF under
hypoxia.26 28 48
However, the present study suggests that HIF-1 is not involved
in the induction of VEGF mRNA by IP because HIF-1 was induced by
infarction but was independent of IP or PKC inhibition.
Consistent with our data, Hossain et
al49 showed that lead
induces the VEGF mRNA expression in human astrocytes through a
PKC-dependent and HIF-1–independent mechanism. Moreover, Shih et
al50 suggested that PKC
upregulates VEGF mRNA in the human glioblastoma cell through the
stabilization of VEGF mRNA. The temporal change of VEGF mRNA in this
study supports the hypothesis in that the IP rapidly and greatly
upregulated VEGF mRNA at 3 to 12 hours after infarction, whereas there
was a smaller extent of VEGF mRNA induction irrespective of the IP
procedure at 1 to 3 days after infarction
(Figures 2D and 2E). Taken together with the temporal
relationship and the correlation by PKC inhibition between the PKC
translocation, VEGF mRNA upregulation, neocapillarization, and infarct
limitation, it is quite likely that the nuclear translocation of PKC
plays a pivotal role in the induction of VEGF mRNA in the
preconditioned rat heart possibly through the stabilization of its
mRNA, thereby inducing angiogenesis and cardioprotection.
In conclusion, our data strongly suggest that IP exerts a
cardioprotective effect through nuclear translocation of PKC and
VEGF-induced
angiogenesis.
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Acknowledgments |
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This work was supported by a Grant-in-Aid from the Ministry of Education, Science and Culture of Japan (12470107) to K.-i.Y.
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Footnotes |
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Original received October 9, 2000; revision received January 25, 2001; accepted February 15, 2001.
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