(Hypertension. 1997;30:1448-1454.)
© 1997 American Heart Association, Inc.
Articles |
Role of Angiotensin II in the Regulation of a Novel Vascular Modulator, Hepatocyte Growth Factor (HGF), in Experimental Hypertensive Rats
From the Department of Geriatric Medicine, Osaka University Medical School, and the Division of Biochemistry, Department of Oncology (K.M., T.M.), Biomedical Research Center, Osaka University Medical School, Osaka, Japan.
Correspondence to Toshio Ogihara, MD, PhD, Chairman and Professor, Department of Geriatric Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita 565, Japan.
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Abstract |
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Abstract Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor that regulates cell growth, cell motility, and morphogenesis of various types of cells, and is thus considered a humoral mediator of epithelial-mesenchymal interactions responsible for morphogenic tissue interactions. We have previously reported that HGF is a novel member of endothelium-specific growth factors whose serum concentration is positively associated with blood pressure in humans. Therefore, we speculated that serum HGF secretion might be elevated in response to high blood pressure as a counter-system against endothelial dysfunction. However, it is difficult to elucidate the role of circulating and tissue HGFs in human hypertension. To address this issue, we measured circulating and tissue HGF concentrations in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at different ages. Serum HGF concentration in SHR was significantly higher than that in WKY at 6, 15, and 25 weeks of age (P<.01). Serum HGF concentration was also significantly positively correlated with blood pressure in SHR (P<.02, r=.455). In contrast, tissue HGF concentrations in heart, aorta, and kidney were significantly decreased in SHR as compared with WKY at 25 weeks of age, when these organs showed hypertrophic changes induced by hypertension (P<.01). Cardiac HGF mRNA was also decreased in SHR as compared with WKY at 25 weeks of age. Moreover, cardiac HGF concentration showed a significant negative correlation with left ventricular (LV) weight (P<.01), whereas serum HGF concentration showed a significant positive correlation with LV weight (P<.05). Interestingly, concentrations of cardiac and vascular angiotensin II, a suppressor of HGF, were increased in SHR as compared with WKY at 25 weeks of age (P<.01). Therefore, we examined the effects of angiotensin blockade on circulating and tissue HGF concentrations, to study the role of angiotensin II in HGF regulation. Administration of an angiotensin-converting enzyme inhibitor (enalapril) and angiotensin II type 1 receptor antagonists (losartan and HR 720) for 6 weeks resulted in a significant increase in cardiac HGF concentration, accompanied by increased cardiac HGF mRNA, and a significant decrease in serum HGF concentration, accompanied by lowered blood pressure and reduced LV weight (P<.01). Here, we demonstrated increased circulating HGF and decreased vascular, cardiac, and renal HGF in SHR as compared with WKY at the maintenance stage of hypertension. Decreased tissue HGF in target organs of hypertension may be due to increased tissue angiotensin II. These results suggest that decreased local HGF production may have an important role in the cardiovascular remodeling of target organs in hypertension, since HGF prevented endothelial injury and promoted angiogenesis. Blockade of angiotensin augmented local decreased cardiovascular HGF in hypertension, potentially resulting in the improvement of endothelial dysfunction.
Key Words: arteriosclerosis • cardiovascular hepatocyte growth factor system • remodeling • endothelial cell
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Introduction |
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Endothelial cells are well known to secrete various vasoactive substances, suggesting that loss or dysfunction of endothelial cells may promote abnormal vascular growth such as in atherosclerosis.1 2 3 Dysfunction of endothelial cells is well known in hypertensive patients,4 5 6 7 thus the loss of substances from endothelial cells might be related to the development and progression of atherosclerosis/arteriosclerosis in hypertension.8 9 Therefore, factors that influence endothelial growth in hypertension have been the center of interest. Among these factors, we have focused on HGF, since HGF is a novel member of the endothelium-specific growth factor family whose mitogenic activity on endothelial cell growth is the most potent among various growth factors.10 HGF is well known to be a mesenchyme-derived pleiotropic factor that regulates cell growth, cell motility, and morphogenesis of various types of cells, and thus is considered a humoral mediator of epithelial-mesenchymal interactions responsible for morphogenic tissue interactions during embryonic development and organogenesis.11 12 13 Of importance, a local HGF system (HGF and its specific receptor c-met) has been identified recently in vascular cells in vivo as well as in vitro.14 Interestingly, our preliminary data revealed that angiotensin II and TGF-ß suppress local HGF production in vascular cells in vitro,15 suggesting the downregulation of the local HGF system in blood vessels in hypertension, since activation of the vascular renin-angiotensin system and upregulation of TGF-ß expression have been reported in hypertensive animals.16 17 18 19 However, there has been no report about the local HGF system in a model of hypertension.
In contrast, clinical studies demonstrated that there is a positive correlation of serum HGF concentration with BP and that serum HGF concentration in hypertensive patients was significantly higher than in normotensive control subjects.20 Therefore, we speculated that serum HGF secretion might be elevated in response to high BP as a counter-system against endothelial dysfunction. However, it is difficult to elucidate the role of circulating and tissue HGFs in human hypertension. In this study, to address these issues, we measured circulating and tissue HGF concentrations in SHR and WKY at different ages. Moreover, to study the role of Ang II in the regulation of HGF, the effects of Ang II blockade were also examined.
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Methods |
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Experiment 1
Male SHR and WKY aged 6, 15, and 25 weeks were obtained from closed colonies at Charles River Japan, Inc (Atsugi, Kanagawa, Japan). Systolic BP was measured by the tail-cuff method. All rats were given regular rat chow (Clea Japan Ltd), with free access to tap water, and housed under identical conditions. Then, the rats were killed. Blood samples were collected by decapitation without anesthesia in prechilled tubes. Before measurement of HGF, serum was stored at -70°C.
Measurement of Serum and Tissue HGF Concentrations
Serum and tissue HGF concentrations were assayed using an EIA
developed recently for use in rats, as described below.21
Blood was drawn after an overnight fast, and serum was collected after
centrifugation. Serum HGF concentration was determined
by enzyme immunoassay using anti-rat HGF antibodies, as described
previously.9 10 11 Anti-rat HGF IgG was coated onto a 96-well
plate (HGF EIA kit, Tokushumeneki Research Center). Serum was added to
each well, and the preparation was incubated for 2 hours at 25°C.
Wells were washed three times with phosphate-buffered saline containing
0.025% Tween 20 (PBS-Tween), then biotinylated rabbit anti-human HGF
IgG was added and the preparation was incubated for 2 hours at 25°C.
After washing with PBS-Tween, wells were incubated with horseradish
peroxidase–conjugated streptoavidin-biotin complex in PBS-Tween. The
enzyme reaction was initiated by adding substrate solution composed of
2.5 mg/mL o-phenylenediamine,
100 mmol/L sodium phosphate, 50 mmol/L citric
acid, and 0.015% H2O2. The enzyme reaction was
halted by adding 1 mol/L H2SO4, and
absorbance at 490 nm was measured.
Tissue HGF concentrations were also assayed. Briefly, the tissues of 6- and 25-week-old rats were promptly removed from the apex without excess fat after perfusion with saline, frozen in liquid nitrogen, and then stored at -70°C until use. On the day of the extraction, the tissue was thawed at 4°C, weighed, and homogenized by Polytron in assay solution. Each specimen was centrifuged at 20 000g for 30 minutes at 4°C, to remove the lysates. Tissue HGF concentration was determined by enzyme immunoassay using anti-rat HGF antibody, as described above.20 21
RNA Analysis
The heart was promptly removed, immediately frozen in liquid
nitrogen, and stored at –80°C before RNA extraction. Total RNA was
extracted from total heart with guanidine thiocyanate by
ultracentrifugation through a dense cushion of CsCl in
a standard manner. For Northern blot analysis, 20 µg of total
RNA was subjected to electrophoresis on 1.5% agarose-formaldehyde
denaturing gel and transferred to a nitrocellulose membrane (Amersham
International plc). The filter was baked, prehybridized, and then
hybridized to full-length cDNA for the rat HGF and rat GAPDH probe
(Amersham International plc), both labeled with 32P. Then
the filter was washed, exposed to x-rays, and analyzed by
densitometry (Shimazu).
Measurement of Ang II
On the day of the extraction, the tissue was thawed at 4°C,
weighed, and homogenized by Polytron in 0.1 N hydrochloric
acid. Each specimen was centrifuged at 20 000g for
30 minutes at 4°C. To extract Ang II, the supernatant was applied to
an octyl mini-column (Amprep C8) that was prewashed with 4 mL methanol
and 4 mL 0.1% TFA. After washing the column with 10 mL 0.1% TFA, Ang
II was eluted with 2 mL ethanol/water/TFA (80:19.9:0.1,
vol/vol/vol). The eluate was dried by a centrifugal
concentrator in a vacuum (CC-181, Tomy). The recovery of Ang II with
this procedure was 98±2% (n=5), which was examined using
125I–Ang II. The data were not corrected for this recovery
because variation of the recovery was negligible as described above.
The resultant residue was resuspended in 100 µL 0.1% TFA.
High-performance liquid chromatography
characterization was performed as previously described.16
Samples of the appropriate fraction were collected, dried in a vacuum
centrifuge, and redissolved in 0.1 mol/L Tris acetate,
pH 7.4, containing 2.6 mmol/L EDTA-2Na, 1
mmol/L phenylmethylsulfonyl fluoride, and 0.1% bovine
serum abumin. Elution times of Ang II, Ang III, and Ang I were 19.0,
20.7, and 23.7 minutes, respectively. Immunoreactive Ang II was
measured by radioimmunoassay using specific Ang II antibody (donated by
Kazuaki Shimamoto, MD, Sapporo Medical College). The sensitivity of
this assay was 0.1 pg/tube. The recovery of Ang II after
high-performance liquid chromatography was
85±5%. The cross-reactivity was 100% for Ang III and less than 0.1%
for Ang I.22
Experiment 2
SHR-SP aged 10 weeks were obtained from Kankyo Bailis Research
(Shiga). All rats were given regular rat chow (Oriental Kobo Co), with
free access to tap water, and housed under identical conditions.
Throughout the experiment, rats were housed in metabolic
cages under light- and temperature-controlled conditions. SHR-SP were
divided into five groups and treated for 6 weeks as follows: vehicle
(distilled water; n=11 rats), HR 720 (1 and 10 mg/kg per day;
n=13), losartan (10 mg/kg per day; n=13), and enalapril
(10 mg/kg per day; n=13). The animals were randomly allocated to
all groups, and the drug was administrated in drinking water. HR 720,
losartan, and enalapril were synthesized and donated by Nippon
Roussel Co, Ltd (Tokyo, Japan). After treatment, the rats were killed
by decapitation and blood was collected. Systolic BP was
measured in conscious rats using the tail-cuff method with a
sphygmomanometer (Softron Co, Ltd). Serum and cardiac HGF
concentrations were measured by EIA, as described above.
Statistical Analysis
All values are expressed as mean±SEM. ANOVA with subsequent
Bonferroni's test was used to determine the significance of
differences in multiple comparisons. Multiple regression
analyses were used to assess the relation between BP and other
parameters. Values of P<.05 were considered
statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Experiment 1
We first evaluated the relationship between serum HGF concentration and BP. As shown in Fig 1a
, serum HGF concentration was significantly increased in SHR as compared
with WKY at 6, 15, and 25 weeks of age. In SHR, serum HGF concentration
was also significantly positively correlated with BP
(r=.455, P<.01, Fig 1b) but not body weight
(data not shown).
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Next, we examined tissue HGF concentration in SHR and WKY at the
developmental stage (6 weeks of age) and maintenance stage (25
weeks of age). Fig 2 shows the presence
of HGF mRNA in various tissues. HGF mRNA was readily detected in heart
(heart in vivo and cardiac myocytes in vitro), kidney, and blood
vessels. As shown in Fig 3, at 25 weeks
of age vascular HGF level was markedly decreased in SHR as compared
with WKY rats (P<.01), whereas at 6 weeks of age it was
increased in SHR as compared with WKY rats (P<.05).
Similarly, HGF level in the heart of SHR was significantly decreased at
25 weeks of age (Fig 4a, P<.01). Cardiac HGF content in SHR was also significantly
lower than that in WKY at 6 weeks of age (P<.05). Cardiac
HGF concentration also showed a significant negative correlation with
LV weight (Fig. 4b, P<.01), whereas there was a significant
positive correlation between serum HGF concentration and LV weight (Fig 4c, P<.05). Cardiac HGF mRNA was also decreased in SHR as
compared with WKY at 25 weeks of age (Fig 5). There was no significant change in
rat GAPDH mRNA between SHR and WKY (data not shown). As shown in Fig 6, there was no significant difference in
renal HGF content between SHR and WKY at 6 weeks of age. In contrast,
renal HGF concentrations were slightly but significantly lower in SHR
than in WKY at 25 weeks of age (P<.05). Since TGF-ß and
Ang II are suppressers of HGF gene expression in various
cells,15 23 24 25 we measured Ang II in various tissues. Of
importance, vascular Ang II was markedly increased in SHR as compared
with WKY rats at 25 weeks of age (WKY, 34.8±1.3 pg/g tissue;
SHR, 43.2±0.7 pg/g tissue, P<.01). Similarly,
cardiac Ang II was also significantly higher in SHR than in WKY at 25
weeks of age (WKY, 14.8±1.3 pg/g tissue; SHR, 20.2±1.7
pg/g tissue, P<.01)
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Experiment 2
We also compared HGF concentrations in WKY, SHR, and SHR-SP at 16
weeks of age to further analyze the effects of BP. Cardiac HGF
concentrations in SHR-SP and SHR were significantly lower than those in
WKY (SHR-SP, 12.1±0.5 ng/g tissue; SHR, 12.4±0.7 ng/g
tissue; WKY; 16.3±1.5 ng/g tissue; P<.01 for SHR-SP
and SHR versus WKY). Therefore, to further study the role of Ang II in
the regulation of the HGF system, we examined the effects of an
angiotensin-converting enzyme inhibitor
(enalapril) and two Ang II receptor type 1 antagonists
(losartan and HR 720) in SHR-SP. Treatment of SHR-SP with HR
720 (10 mg), losartan, and enalapril for 6 weeks significantly
decreased systolic BP (P<.01), whereas there was no
significant difference in systolic BP between vehicle and HR
720 (1 mg), as shown in Fig 7. Neither
body weight nor heart rate differed significantly among all groups
(data not shown). As shown in Fig 8a, the
administration of HR 720 (10 mg), losartan, and enalapril
resulted in a significant decrease in LV weight/body weight, whereas
the administration of HR 720 (1 mg) failed to decrease LV weight
(P<.01). In contrast, cardiac HGF concentration was
significantly increased by treatment with HR 720 (10 mg),
losartan, and enalapril, but not HR 720 (1 mg) (Fig 8b, P<.01). This increase in cardiac HGF concentration in rats
treated with HR 720 (10 mg), losartan, and enalapril was due to
increased HGF mRNA level as compared with that of vehicle-treated rats
as assessed by Northern blotting (Fig 8c and 8d). Finally, serum HGF
concentration was measured. As shown in Fig 9, serum HGF concentration was
significantly decreased by the administration of HR 720 (10 mg),
losartan, and enalapril, but not HR 720 (1 mg)
(P<.01), consistent with the decrease in BP.
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Discussion |
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In this study, we measured renal, cardiac, and vascular HGF concentrations in SHR and WKY because these organs are well known targets for hypertension. Interestingly, our present studies demonstrated decreased renal, cardiac, and vascular HGF concentrations at the time (25 weeks old) that these organs revealed hypertrophic changes due to hypertension. Since it is well known that endothelial cells regulate vascular tone and structure,1 2 3 disruption or dysfunction of endothelial cells results in loss of multiple endothelium-derived substances (prostaglandin I2, nitric oxide, CNP), resulting in a shift of the balance of vascular smooth muscle cell growth to abnormal growth such as in atherosclerosis.1 2 3 If production of local HGF, an endothelial protectant, were decreased, dysfunction of endothelial cells might be accelerated. The decreased local HGF production in blood vessels in SHR demonstrated in this study may be related to the development of vascular hypertrophy. Moreover, a decreased number of capillary vessels in the heart has also been reported in hypertension.26 27 28 29 Of importance, a recent study revealed the potential role of HGF in promoting angiogenesis.30 31 Therefore, decreased local HGF production in the heart may also be related to cardiac remodeling induced by hypertension. The significant negative correlation between cardiac HGF concentration and LV weight observed in this study also supports this possibility. Moreover, the present study revealed a differential expression of HGF in aorta as compared with that in heart and kidney, according to the age of the rat. Although further studies are necessary, local HGF production might have a role in the development of these organs.
Why was local HGF production decreased in hypertrophied organs? Our current studies partially addressed the mechanisms by which local HGF concentration was decreased in hypertension, as discussed below. Our preliminary data showed that Ang II strongly inhibited HGF production in vascular cells in vitro.15 In this study, increased Ang II in the heart and blood vessels of SHR was observed at 25 weeks of age, whereas local HGF concentration in the heart and blood vessels was decreased in SHR. Moreover, our hypothesis is supported by the observation that blockade of the angiotensin system by the administration of an angiotensin-converting enzyme inhibitor and Ang II receptor antagonists increased cardiac HGF in accordance with the improvement of LV hypertrophy. Taken together, activation of local vascular angiotensin in vascular and cardiac cells may negatively regulate local HGF production, which might play a role in organ protection in local tissues.
On the other hand, HGF as well as basic fibroblast growth factor work
as survival factors in endothelial
cells.32 33 The addition of recombinant HGF can attenuate
endothelial cell death induced by serum-free treatment
and TNF-
, suggesting a potential role of the local HGF system in
endothelial function.33 Moreover,
decreased local HGF production in vascular cells by high
D-glucose treatment might accelerate endothelial
dysfunction observed in diabetes mellitus.34 On the other
hand, the administration of angiotensin-converting enzyme
inhibitors and Ang II receptor antagonists has
been reported to improve endothelial dysfunction in
diabetes mellitus and hypertension.17 28 30 35 36 37 Taken
together, increased local HGF production by blockade of
angiotensin may contribute to the improvement of
endothelial dysfunction.
Here we demonstrated increased serum concentration and decreased cardiovascular tissue concentrations of HGF in SHR as compared with WKY rats at ages at which target organs of hypertension showed hypertrophic changes. Decreased tissue HGF concentration in target organs of hypertension may be due to increased tissue Ang II. These results suggest that decreased tissue HGF concentration may have a role in cardiovascular remodeling and that circulating HGF might be elevated in response to high BP as a counter-system against cardiovascular dysfunction. Blockade of the renin-angiotensin system augmented local cardiovascular HGF concentration, potentially resulting in the improvement of endothelial dysfunction. Our present study provides evidence of a new aspect of Ang II function in cardiovascular organ damage through decreased local HGF production.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was partially supported by grants from the Japan Society for the Promotion of Science, the Osaka Kidney Foundation (OKF 96-0002), ONO Medical Research Foundation, and Japan Heart Foundation: Pfizer Pharmaceuticals Grant for Research on coronary artery disease. Dr Ryuichi Morishita is the recipient of a Harry Goldblatt Award from the Council of High Blood Pressure of the American Heart Association. We wish to thank Chihiro Noguchi for their excellent technical assistance.
Received September 19, 1996; first decision October 15, 1996; accepted June 9, 1997.
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References |
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 D. You, C. Cochain, C. Loinard, J. Vilar, B. Mees, M. Duriez, B. I. Levy, and J.-S. Silvestre Hypertension Impairs Postnatal Vasculogenesis: Role of Antihypertensive Agents Hypertension, June 1, 2008; 51(6): 1537 - 1544. [Abstract] [Full Text] [PDF]
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 S. Takeshita, H. Tomiyama, N. Yokoyama, Y. Kawamura, T. Furukawa, Y. Ishigai, T. Shibano, T. Isshiki, and T. Sato Angiotensin-converting enzyme inhibition improves defective angiogenesis in the ischemic limb of spontaneously hypertensive rats Cardiovasc Res, November 1, 2001; 52(2): 314 - 320. [Abstract] [Full Text] [PDF]
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K. Matsumoto, R. Morishita, A. Moriguchi, N. Tomita, M. Aoki, H. Sakonjo, K. Matsumoto, T. Nakamura, J. Higaki, and T. Ogihara Inhibition of Neointima by Angiotensin-Converting Enzyme Inhibitor in Porcine Coronary Artery Balloon-Injury Model Hypertension, February 1, 2001; 37(2): 270 - 274. [Abstract] [Full Text] [PDF]
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 Y. Taniyama, R. Morishita, H. Nakagami, A. Moriguchi, H. Sakonjo, Shokei-Kim, K. Matsumoto, T. Nakamura, J. Higaki, and T. Ogihara Potential Contribution of a Novel Antifibrotic Factor, Hepatocyte Growth Factor, to Prevention of Myocardial Fibrosis by Angiotensin II Blockade in Cardiomyopathic Hamsters Circulation, July 11, 2000; 102(2): 246 - 252. [Abstract] [Full Text] [PDF]
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 S. Yasuda, Y. Goto, T. Baba, T. Satoh, H. Sumida, S. Miyazaki, and H. Nonogi Enhanced secretion of cardiac hepatocyte growth factor from an infarct region is associated with less severe ventricular enlargement and improved cardiac function J. Am. Coll. Cardiol., July 1, 2000; 36(1): 115 - 121. [Abstract] [Full Text] [PDF]
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 W. B Strawn, R. H Dean, and C. M Ferrario Novel mechanisms linking angiotensin II and early atherogenesis Journal of Renin-Angiotensin-Aldosterone System, March 1, 2000; 1(1): 11 - 17. [PDF]
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 R. Busse and I. Fleming A critical look at cardiovascular translational research Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1655 - H1660. [Full Text] [PDF]
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 M.A. Breider, A.W. Gough, J.R. Haskins, G. Sobocinski, and F.A. De La Iglesia Troglitazone-Induced Heart and Adipose Tissue Cell Proliferation in Mice Toxicol Pathol, September 1, 1999; 27(5): 545 - 552. [Abstract] [PDF]
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K. Matsumoto, R. Morishita, A. Moriguchi, N. Tomita, Y. Yo, T. Nishii, K. Matsumoto, T. Nakamura, J. Higaki, and T. Ogihara Prevention of Renal Damage by Angiotensin II Blockade, Accompanied by Increased Renal Hepatocyte Growth Factor in Experimental Hypertensive Rats Hypertension, August 1, 1999; 34(2): 279 - 284. [Abstract] [Full Text] [PDF]
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 Y. Yoshitomi, S. Kojima, T. Umemoto, K. Kubo, Y. Matsumoto, M. Yano, T. Sugi, and M. Kuramochi Serum Hepatocyte Growth Factor in Patients with Peripheral Arterial Occlusive Disease J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2425 - 2428. [Abstract] [Full Text]
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S. Yasuda, Y. Goto, H. Sumida, T. Noguchi, T. Baba, S. Miyazaki, and H. Nonogi Angiotensin-Converting Enzyme Inhibition Restores Hepatocyte Growth Factor Production in Patients With Congestive Heart Failure Hypertension, June 1, 1999; 33(6): 1374 - 1378. [Abstract] [Full Text] [PDF]
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