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CARDIOVASCULAR
Departments of Cardiovascular Research (H.J., R.Y., W.L., R.K.O., N.F.P.), Molecular Oncology (R.S., Z.Z.), Pathology (D.A.E.), and Recovery Science (D.K.), Genentech, Inc., South San Francisco, California
Received July 31, 2002; accepted October 24, 2002.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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).
Subsequently, several functions have been ascribed to HGF, including
motogenesis, morphogenesis, hematopoiesis, antiapoptosis, and angiogenesis
(Bussolino et al., 1992;
Grant et al., 1993;
Zarnegar and Michalopulos,
1995; Matsumoto and Nakamura,
1996; Kopp, 1998;
Balkovetzz and Lipschutz, 1999). HGF has also been shown to induce tissue
regeneration in a variety of organs, particularly in the liver
(Comoglio, 1993;
Matsumoto and Nakamura, 1997).
These multipotent activities of HGF are mediated by stimulating the tyrosine
kinase activity of its specific receptor, which is encoded by the
c-met proto-oncogene (Bottaro et
al., 1991; Naldini et al.,
1991).
Recently, HGF has been given increasing attention in cardiac diseases
(Mastusmori et al., 1996;
Ono et al., 1997; Ueda et al.,
1999,
2001;
Aoki et al., 2000;
Nakamura et al., 2000; Yasuda
et al., 1999,
2000;
Taniyama et al., 2000;
Zhu et al., 2000). Circulating
levels of HGF are substantially elevated in rats
(Ono et al., 1997) and in
humans after acute myocardial infarction (MI)
(Mastusmori et al., 1996;
Molnar et al., 2000; Soeki et
al.,
2000a,b).
In the rat, plasma HGF levels increase in a biphasic manner after cardiac
ischemia reperfusion, peaking at 3 h and increasing again at 24 h
(Ono et al., 1997), and data
from previous studies indicated that HGF can be cardioprotective toward acute
ischemia-reperfusion injury. Early administration of HGF in a rat model of
cardiac ischemia reperfusion reduced infarct size and improved short-term
cardiac performance (Nakamura et al.,
2000).
It is also known that myocardial levels of HGF and c-Met mRNA and protein
are elevated in the week after myocardial infarction
(Ono et al., 1997;
Ueda et al., 2001). Cardiac
mRNA abundance for HGF was increased for up to 5 days after MI in a model of 1
h of cardiac ischemia followed by reperfusion
(Ono et al., 1997).
Immunohistochemical staining for HGF at 24 and 48 h post-MI showed intense
staining in the cytoplasm of endothelial cells and in interstitial cells,
including infiltrating macrophage. c-Met transcript levels were also increased
for 5 days in the ischemic heart. Immunohistochemical analyses showed positive
staining for c-Met in capillary endothelial cells
(Ono et al., 1997). In a
recent study, both HGF and c-Met mRNA levels in the left ventricle
substantially increased from 6 h after left coronary ligation and continued to
increase for up to at least 7 days in rats with MI
(Ueda et al., 2001). The c-Met
receptor was expressed in cardiomocytes localized in the border regions of the
viable myocardium and in noninfarcted regions, suggesting that myocytes may be
a primary target of endogenous HGF.
The observations that HGF and c-Met are persistently induced in the
myocardium, well past the acute phase of ischemic injury, led us to
hypothesize that HGF may have beneficial effects in ischemic cardiomyopathy,
independent of those that influence infarct size. To test this we used a rat
model of cardiac ischemia/reperfusion where the duration of ischemia was 2 h,
sufficient time to produce infarcts large enough to cause progression to heart
failure. HGF was administered to MI rats for 6 days, beginning the day after
surgery so as to avoid having a direct effect on infarct size. The long-term
effects of HGF treatment on cardiac function were then determined 8 weeks
post-MI, because our previous studies have shown that untreated rats with
moderate-large myocardial infarction develop evident heart failure at 8 weeks
in this model (Yang et al.,
1995; Jin et al.,
2001). Our results suggest that HGF improves cardiac function in
experimental heart failure induced by MI.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Animal Model. Male Sprague-Dawley rats (7–8 weeks of age;
Charles River Laboratories, Inc., Wilmington, MA) were acclimated to the
facility for at least 1 week before surgery. Rats were fed a pelleted rat chow
and water ad libitum, and housed in a light- and temperature-controlled room.
The procedure used for left coronary ligation has been described in detail
elsewhere (Pfeffer et al.,
1979). In brief, the rats were anesthetized with ketamine
hydrochloride (100 mg/kg i.p.) and xylazine (10 mg/kg i.p.), intubated via
tracheotomy, and ventilated by a respirator (model 683; Harvard Apparatus,
Inc., Holliston, MA). After a left-sided thoracotomy, the left coronary artery
was ligated approximately 2 mm from its origin with a 7-0 silk suture. Two
hours after ligation, the ligature was released for reperfusion.
Time Course of Cardiac Gene Expression of HGF and c-Met. The time
points used were 3 h, 8 h, 1 day, 3 days, 1 week, 2 weeks, and 1 month after
left coronary ligation or sham operation (n = 6 at each time point in
each group). ECG analyses were used to identify rats with moderate-to-large
infarcts (Yang et al., 1995)
for time points 1 day after surgery or longer. For the 3and 8-h time points
serum troponin T levels were used to identify rats with evidence of infarcts.
In a pilot study, we found a significant correlation between serum troponin T
levels and infarct size at3h(r = 0.675, P < 0.001), 4 h
(r = 0.849, P < 0.0001), and 24 h (r = 0.916,
P < 0.0001) after MI/reperfusion. The serum troponin T levels at 3
and 8 h were markedly different between MI rats (304.32 ± 58.99 mg/dl)
and sham controls (1.08 ± 0.13 mg/dl). ECG on days 1 to 30 after
surgery showed significant abnormal Q wave in at least three precordial leads
in MI rats but no abnormalities in sham-operated animals.
At the various time points the rats were killed and the hearts were
removed. The left ventricular free wall and septum were frozen in liquid
nitrogen and stored at –70°C until used. Total RNA was isolated from
the samples using the RNeasy maxi kit (QIAGEN, Valencia, CA). Relative mRNA
abundance of the target genes was determined by real-time reverse
transcription-polymerase chain reaction using a TaqMan model 7700 sequence
detector (ABI-PerkinElmer, Foster City, CA) as described previously
(Winer et al., 1999).
Expression levels for each gene were normalized to ribosomal protein L19,
which was unaffected by MI.
HGF Administration. One day after left coronary
ligation/reperfusion, animals with ECG evidence of moderate-to-large infarcts
were randomly assigned to receive either intravenous infusion of saline
vehicle or recombinant human HGF (Genentech, Inc., South San Francisco, CA) at
0.45 mg/kg/day for 6 days by implanted osmotic pump (model 2001; Alza, Palo
Alto, CA) with a catheter into the right jugular vein. The total dose of HGF
was equivalent to the dose that produced beneficial effects in rats with
myocardial ischemia/reperfusion (Nakamura
et al., 2000). Sham-operated rats did not receive treatment. The
animals were followed up for either 1 week or 8 weeks after the initiation of
treatment. At 1 week, blood (1 ml) was collected for measurement of plasma HGF
and serum biochemistries for liver and kidney function, and rats were killed
and the heart and other organs were removed and weighed. At 8 weeks,
hemodynamics and cardiac function were measured before blood collection and
organ harvest as described above.
Assessment of Hemodynamics and Cardiac Function. Under anesthesia
with ketamine (80 mg/kg) and xylazine (10 mg/kg) given intraperitoneally, rats
were intubated and ventilated with a respirator. A catheter (polyethylene-10
fused with polyethylene-50) filled with heparin-saline (50 U/ml) was implanted
into the abdominal aorta via the right femoral artery for measurement of mean
arterial pressure (MAP) and heart rate (HR). After a right-sided thoracotomy,
an ultrasonic perivascular flowprobe (2.5S; Transonic Systems, Inc., Ithaca,
NY) was placed around the ascending aorta
(Yang et al., 1998). The
catheter and flowprobe cable were exteriorized and fixed at the back of the
neck. All rats were housed individually after surgery.
One day after implantation, MAP and HR were measured with a model P23 XL pressure transducer (Viggo-Spectramed, Oxnard, CA) coupled to a polygraph, and cardiac output was determined with a model T 201 flowmeter (Transonic Systems, Inc.) simultaneously in conscious, unrestrained rats. Stroke volume was calculated as cardiac output divided by HR, cardiac index as cardiac output divided by BW, stroke volume index as stroke volume divided by BW, and systemic vascular resistance as MAP divided by cardiac index.
Infarct Size Measurements. Infarct size was determined by
morphometric analysis in the end of the experiment after blood collection. The
right ventricular free wall was dissected from the left ventricle. The left
ventricle was cut in four transverse slices from apex to base. Five-micrometer
sections were cut and stained with Massons' trichrome stain and mounted
(Yang et al., 1995). The
endocardial and epicardial circumferences of the infarcted and non-infarcted
regions were determined with a planimeter digital image analyzer. The
infarcted circumference and the total left ventricular circumference of all
four slices for both endocardial and epicardial surfaces were summed and
expressed as a percentage of infarcted circumference to total circumference
for determination of infarct size.
Blood Assay. Plasma concentrations of recombinant human HGF were
measured using a specific sandwich enzyme-linked immunosorbent assay
(Roos et al., 1995). The
antibody used for the assay was specific for human HGF. Serum biochemistries
were measured on a Monarch model 761 microcentrifugal chemistry analyzer
(Instrumentation Laboratories, Lexington, MA).
Statistical Analysis. Results are expressed as mean ± S.E.M. One-way analysis of variance was performed to assess differences in parameters between groups. Significant differences were then subjected to post hoc analysis using the Newman-Keuls method. P < 0.05 was considered significant.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Effects of HGF Observed at 1 Week. HGF was administered to rats with
MI, commencing the day after ischemia/reperfusion and continuing for 6 days.
The total amount of HGF given was equivalent to the dose previously shown to
produce beneficial results toward acute cardiac ischemic injury
(Nakamura et al., 2000). On
day 7 after the initiation of HGF infusion, there was a 100-fold increase in
plasma levels of HGF in the HGF-treated MI rats compared with those with
vehicle-treated MI and the sham-operated controls (P < 0.01;
Fig. 2). BW was not different
in the three groups (Table 1).
As expected, HGF treatment resulted in significant liver growth. The liver
weight to body weight ratio of the HGFtreated MI group was 52 and 57% greater
than that of the untreated sham control and vehicle-treated MI groups
respectively (P < 0.01). The ventricular weight-to-body weight
ratio of the MI + HGF group was also significantly greater than that of the
sham control group, but not different from the MI + vehicle group. The ratios
of kidney and spleen weights to body weight were not different between
groups.
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The liver growth observed in the HGF-treated rats was not associated with
an increase in serum levels of liver enzymes. The serum concentrations of
alanine amino-transferase, amylase, aspartate amino-transferase, and
-glutamyltransferase were comparable in the three groups. Serum total
protein and albumin were significantly elevated and the serum concentration of
alkaline phosphatase was significantly reduced from control levels in the MI +
HGF rats. Kidney function, as assessed by the blood urea nitrogen and
creatinine serum concentrations, was unaffected by MI or HGF. Rats with
HGF-treated MI had significantly greater total protein in their serum compared
with vehicle-treated MI and sham animals.
Effects of HGF Observed at 8 Weeks. At 8 weeks, plasma levels of HGF were the same in the three groups (Fig. 2). There was also no significant difference in BW (Table 2). The ratio of liver weight to BW was still increased in the MI + HGF group compared with the sham group (P < 0.05), but not compared with the MI + vehicle group. There was an increase in the ratio of ventricle weight to BW in both MI groups compared with sham controls (P < 0.01 or 0.05), indicating that MI produced ventricular hypertrophy. Neither MI nor HGF had effects on kidney and spleen weights (Table 2).
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MAP and HR were comparable in the three experimental groups (Table 2). Rats with vehicle-treated MI had clear evidence of heart failure (Fig. 3). Their cardiac index (CI) and stroke volume index (SVI) were lower than that of sham control rats (P < 0.01), and their systemic vascular resistance (SVR) was higher (P < 0.01). HGF treatment attenuated the effects of MI. There was no significant difference in CI, SVI, or SVR between the MI + HGF and sham control groups. Histological examination revealed that the beneficial effects of HGF on cardiac performance were not a result of a reduction in infarct size because that parameter was the same between the two MI groups (Fig. 4). Peripheral areas of the infarcts displayed new vessels in growth as part of the healing process, but there were no qualitative differences in vascularization in the infarcts or the viable myocardium between the MI rats treated with HGF and vehicle control.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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The premise for this work was based on the observations that myocardial HGF
and c-Met were induced for several days after MI
(Ono et al., 1997;
Ueda et al., 2001) and that
the peak levels occurred well past the acute phase of injury. Our hypothesis
was that local HGF production may have beneficial effects on long-term outcome
and that supplemental addition of HGF could enhance these effects.
HGF was previously shown to be cardioprotective toward acute cardiac
ischemia-reperfusion injury. Ueda et al.
(1999) showed that gene
transfection of HGF into rat hearts attenuated subsequent ischemia injury.
Nakamura et al. (2000) later
found that neutralizing antibodies to HGF administered to rats before and
after coronary artery ligation and reperfusion resulted in an increase in
infarct size (Nakamura et al.,
2000). They further showed that HGF administration, initiated
immediately after a short period (20 min) of cardiac ischemia followed by
reperfusion, decreased infarct size, and increased short-term cardiac
performance, measured 48 h postsurgery. This effect was attributable to the
ability of HGF to suppress cardiomyocyte apoptosis.
The purpose of this study was to determine the effects of HGF on the
progression of MI to heart failure, thus a longer period of ischemia (2 h) was
used and the onset of treatment was delayed until the day after coronary
artery ligation. The mechanism by which HGF treatment improved cardiac
performance in this model remains to be determined; however, the possibility
of a reduction in apoptosis might be considered although infarct size was
unaffected by the treatment. Myocyte cell death contributes not only to
infarct size but also to myocardial remodeling after MI
(Colucci, 1996;
Fliss and Gattinger, 1996).
Major pathophysiological events after acute MI include hypertrophic responses
of cardiomyocytes in the surviving portion of the ventricle, followed by
ventricular dilation characterized by a diminished cardiac function, and then
heart failure. The underlying mechanism responsible for cardiac dilation has
been linked to myocyte cell death in the surviving regions
(Cheng et al., 1996;
Ueda et al., 2001). As an
antiapoptosis factor, HGF could maintain cardiac function by suppressing
myocyte cell death (Ueda et al.,
2001). In vitro studies have demonstrated that c-Met receptor
expression is induced in cardiomyocytes and that HGF has cytoprotective
effects on mature cardiac myocytes in a dose-dependent manner
(Ueda et al., 2001). This
indicates that HGF exerts a direct protective action on cardiac myocytes. The
intracellular signals leading to antiapoptosis in cardiac myocytes by HGF may
be through the ERK pathway but not PI3-Akt pathway
(Nakamura et al., 2000;
Ueda et al., 2001). A recent
clinical study suggests HGF may play an important role in human heart failure.
It has been found that cardiac HGF secretion remains enhanced up to 4 weeks
after infarction in patients with MI
(Yasuda et al., 2000). The HGF
secretion from infarct regions correlates inversely with the variables of
heart function, i.e., the patients post-MI with enhanced cardiac HGF
production in MI regions are associated with attenuated ventricular remodeling
and improved cardiac function, indicating the HGF system may play a
cardioprotective role during ventricular remodeling.
Because of the significant induction of endogenous cardiac HGF and c-Met post-MI, it is tempting to assume supplemental HGF exerted its effects directly on the heart. HGF is an important mitogen for hepatocytes, however, and we observed an approximate 50% increase in LW/BW in the MI + HGF group 1 week post-MI. The serum levels of total protein and albumin in HGF-treated rats were also 1.4 times that of rats with vehicle-treated MI. Thus, we cannot rule out the possibility that the results we observed on cardiac performance were secondary to HGF effects on liver growth and plasma protein levels. However, at the time, cardiac performance and hemodynamics were measured (8 weeks post-MI), there was no significant difference in LW/BW between the HGF-treated and vehicle-treated MI groups.
HGF production is influenced by the renin-angiotensin system
(Nakamura et al., 1996;
Yasuda et al., 1999).
Angiotensin II plays an important role in the pathophysiology of heart
failure, elevating vascular resistance, enhancing sympathetic activity,
promoting cardiac hypertrophy and enlargement, and/or increasing water
retention. More importantly, angiotensin II at the tissue level contributes to
the modulation of heart and vessel remodeling
(Yasuda et al., 1999).
Clinical evidence indicates that blockade of the reninangiotensin system can
improve hemodynamics, cardiac remodeling and performance, relieve symptoms,
and reduce mortality in patients with congestive heart failure. Recent studies
have shown that angiotensin II is a strong suppressor of HGF
(Nakamura et al., 1996), and
HGF production is significantly impaired in patients with chronic congestive
heart failure post-MI (Yasuda et al.,
1999). Treatment with ACE inhibitors (ACE-I) restores the impaired
HGF production in these patients, suggesting that the restoration of HGF
production may play a role in mediating the functional repair process of ACE-I
(Yasuda et al., 1999). Our
findings may provide direct evidence that supplement addition of HGF
significantly attenuates development of heart failure after moderate-large
myocardial infarction.
Although the data presented herein are generally supportive of the use of
systemically administered HGF for treatment of ischemic heart disease or heart
failure, there are several potential problems that may be associated with this
therapeutic approach. First, HGF administration can promote liver growth. It
was previously shown that exogenous HGF caused a dose-dependent increase in
liver weight in normal and partially hepatectomized animals
(Fujiwara et al., 1993;
Ishii et al., 1995;
Roos et al., 1995). The
mechanism for this effect is HGF-induced hepatocyte proliferation, although a
trophic effect may also be involved (Roos
et al., 1995). Our results showed that intravenous infusion of HGF
for 1 week increased liver weigh by 57% in MI rats, but there was no
difference in liver weight between vehicle- and HGF-treated MI rats 7 weeks
after dosing, suggesting that liver overgrowth induced by HGF is reversible.
In addition, the HGF-induced liver enlargement was associated with normal
liver/kidney function. Furthermore, HGF has been shown to attenuate hepatic
ischemia-reperfusion injury and liver dysfunction in rats
(Sakakura et al., 2000;
Oe et al., 2001). Taken
together, these data suggest that if the effects of HGF on the liver growth
are minimized by dosing, they may be acceptable with caution.
A second issue to consider is the effects of HGF on serum biochemistry.
Consistent with previous studies (Ishii et
al., 1995; Roos et al.,
1995), the present study showed exogenously administered HGF
elevated serum total protein and albumin levels and reduced serum alkaline
phosphatase. It is known that the liver is the major source of serum proteins.
The detailed mechanism by which HGF increases the contents of serum proteins
synthesized in the liver is unclear, but it is likely that HGF may stimulate
albumin synthesis in hepatocytes through transcriptional activation
(Ishii et al., 1995). HGF has
also been reported to increase serum prothrombin and hepaplastin in addition
to albumin (Ishii et al.,
1995). These effects of HGF could result in a hypercoagulable
state, and this is an area where further research is warranted. The mechanism
for the HGF-induced reduction of alkaline phosphatase is unknown
(Roos et al., 1995). Finally,
because stimulation of c-Met by its ligand HGF can lead to angiogenesis,
proliferation, enhanced cell motility, invasion, and eventual metastasis
(Maulik et al., 2002), HGF
should not be administered to patients with active neoplasms.
In summary, HGF treatment for 6 days beginning the day after myocardial ischemia/reperfusion enhanced cardiac function without altering infarct size, measured at 8 weeks post-MI. The data suggest that HGF exerts beneficial effects in experimental heart failure, however, the mechanism for the effect of HGF is unclear. Histological analysis showed no qualitative difference between HGFand vehicle-treated groups with regard to vascularization in the infarcts and viable myocardia. This does not seem to be consistent with the hypothesis that myocardial angiogenesis contributes to the HGF-induced improvement in cardiac performance. Subsequent studies are needed to elucidate the direct protective mechanism of HGF on cardiomyocytes in ischemia cardiomyopthy and to determine whether systemic administration of HGF induces myocardial angiogenesis. In addition, because HGF production may be linked to benefits of treatment with ACE inhibition in heart failure, further studies are also warranted to test a possible cumulative effect of HGF and ACE inhibition.
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Footnotes |
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ABBREVIATIONS: HGF, hepatocyte growth factor; MI, myocardial infarction; MAP, mean arterial pressure; HR, heart rate; BW, body weight; LW, liver weight; CI, cardiac index; SVI, stroke volume index; SVR, systemic vascular resistance; ACE, angiotensin-converting enzyme.
Address correspondence to: Dr. Hongkui Jin, Department of Cardiovascular Research, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. E-mail address: hkj{at}gene.com
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