doi: 10.1161/hc3601.094304
(Circulation. 2001;104:1274.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Significance of Chymase-Dependent Angiotensin II–Forming Pathway in the Development of Vascular Proliferation
From the Departments of Pharmacology (M.N., S.T., D.J., A.Y., M.S., M.Y., M.M.) and Thoracic and Cardiovascular Surgery (M.N., A.Y., Y.S., K.K., K.A., S.S.), Osaka Medical College, and the Department of Pharmacology, Osaka City University Medical School (S.K., H.I.), Osaka, Japan.
Correspondence to Mizuo Miyazaki, MD, PhD, Department of Pharmacology, Osaka Medical College, Osaka 569-8686, Japan. E-mail pha010{at}art.osaka-med.ac.jp
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Abstract |
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Background— Vascular tissues of humans and dogs contain chymase as an angiotensin II–forming enzyme. In this study, we investigated whether chymase-dependent angiotensin II formation plays a crucial role in the development of vascular proliferation in dog grafted veins.
Methods and Results— The right external jugular vein of dogs was grafted to the ipsilateral carotid artery. As a control group, the right external jugular veins in dogs that had not received grafts were used. In the chymase inhibitor–treated group, the vein was infiltrated with 10 µmol/L Suc-Val-Pro-PheP(OPh)2 and was grafted to the carotid artery. In the placebo-treated group, ACE activity in the grafted veins was significantly lower than that in the control veins up to 7 days after the operation, whereas chymase activity was increased significantly. After 7 days, the mRNA levels of collagen I, collagen III, and fibronectin, all of which are induced by an increase of angiotensin II action, were significantly increased in the grafted veins, and the intima-media ratio of the grafted veins was also increased. In the chymase inhibitor–treated group, the chymase activity in the grafted veins 7 days after the operation was suppressed to 12.1%. The elevated mRNA levels of fibronectin, collagen I, and collagen III in the grafted veins were significantly suppressed by treatment with the chymase inhibitor, and the intima-media ratio was also decreased significantly.
Conclusions— We demonstrate for the first time that chymase-dependent angiotensin II formation plays an important role in the development of vascular proliferation in the grafted veins.
Key Words: angiotensin • enzymes • chymase • grafting
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Introduction |
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Coronary artery bypass graft surgery has offered relief to patients with ischemic heart disease.1,2 The internal thoracic artery (ITA) and saphenous vein (SV) have frequently been used as coronary artery bypass conduits. The clinical benefits are gradually lost, however, and graft function deteriorates, resulting in recurrence of clinical symptoms.3,4 The poor performance of the SV compared with the ITA is well known; the disorder is called vein graft disease.3,4 Although early occlusions of the SV are thought to be chiefly due to intimal hyperplasia, the mechanism of vascular proliferation is unclear, and drugs that prevent vascular proliferation are in great demand.
Angiotensin (Ang) II plays an important role in vascular proliferation via the induction of extracellular matrix and growth factors.5,6 For example, in a rat model, neointima formation in vessels injured by a catheter was prevented by an Ang II type 1 (AT1) receptor antagonist, and the expression of extracellular matrix and growth factors was suppressed.7 Such findings were also reported when an ACE inhibitor was used in the rat model.8 Clinical trials of ACE inhibitor for preventing restenosis after percutaneous transluminal coronary angioplasty, however, were unsuccessful.9 In graft experimental models, an ACE inhibitor was effective in preventing vascular proliferation in rats, whereas in baboons, it was not.10,11 Such species differences in the effects of ACE inhibitors on neointimal formation may depend on species differences in the Ang II–forming pathways. Rat vascular tissues contain ACE as the only Ang II–forming enzyme, whereas vascular tissues of humans, monkeys, dogs, and hamsters contain chymase in addition to ACE as Ang II–forming enzymes.12–14 Therefore, it is thought that ACE inhibitors could not suppress chymase-dependent Ang II formation, resulting in vascular proliferation in primate vessels despite the prevention of such proliferation in rats. In fact, in dog vessels injured by a catheter, an AT1 receptor antagonist was effective in preventing intimal formation, but an ACE inhibitor was ineffective.15 It has been unclear, however, whether Ang II formation via the chymase pathway plays an important role in developing vascular proliferation.
In the present study, we investigated the levels of the Ang II–forming enzymes chymase and ACE and the Ang II–inducing mRNA of extracellular matrix and growth factors in dog grafted veins and studied the role of chymase-dependent Ang II formation on the development of vascular proliferation.
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Methods |
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Drugs and cDNA Probes
A specific chymase inhibitor, Suc-Val-Pro-PheP(OPh)2, was a gift from Dr Oleksyszyn, Akoslogic Inc, Mass.16 cDNA probes used were as follows: rat transforming growth factor-ß1 (TGF-ß1) cDNA (a 1.0-kb HindIII/XbaI fragment)17; rat fibronectin cDNA (a 0.27-kb HindIII/EcoRI fragment)18; rat
1 (I) collagen cDNA (a 1.3-kb PstI/BamHI fragment)19; mouse 1 (III) collagen cDNA (a 1.8-kb EcoRI/EcoRI fragment)20; and rat cDNA for vascular endothelial growth factor (VEGF).21
Animal Model of Vein Graft
Forty-three beagle dogs weighing 9 to 13 kg were obtained from Japan SLC. The animals were anesthetized with sodium pentobarbital (35 mg/kg IV). In the placebo-treated group, the right external jugular vein was removed and was infiltrated for 20 minutes in saline containing isosorbide dinitrate (50 mg/mL) and dipyridamole (100 mg/mL). In the group treated with the chymase inhibitor, the vein was infiltrated for 20 minutes in the solution used for the placebo group, but with the addition of Suc-Val-Pro-PheP(OPh)2 (10 µmol/L). Then, the vein was grafted to the ipsilateral carotid artery. The experimental procedures for animals were in accordance with the Guide for the Care and Use of Laboratory Animals (Animal Research Laboratory, Osaka Medical College).
Preparation of Vascular Tissue
As a control group, 5 dogs that had not received grafts were anesthetized, and the right external jugular vein was removed. At 1, 3, 7, 14, and 28 days after the operation, the animals (each group comprised 5 dogs) were anesthetized, and then the grafted veins were removed. In the group treated with the chymase inhibitor (n=5), the grafted veins were removed 7 days after the operation.
Extraction for Enzyme Assay
The vein was homogenized in 20 mmol/L sodium phosphate buffer, pH 7.4. The homogenate was centrifuged, and the pellet was resuspended in 10 mmol/L sodium phosphate buffer, pH 7.4, containing 2 mol/L KCl and 0.1% Nonidet P-40. The supernatant was used for measurement of ACE and chymase activities.15
Measurements of Enzyme Activities
The ACE activity was measured by incubating tissue extracts with 5 mmol/L hippuryl-His-Leu in 10 mmol/L phosphate buffer, pH 8.3, containing 800 mmol/L NaCl.15 The chymase activity was measured by incubation of tissue extracts with 4 mmol/L Ang I in 150 mmol/L borax-borate buffer, pH 8.5, containing 8 mmol/L dipyridyl, 770 µmol/L diisopropyl phosphorofluoridate, and 5 mmol/L EDTA.15 Protein concentration was assayed with BCA Protein Assay Reagents (Pierce).
Determination of Ang II Concentrations
As a control group, 4 dogs that had not received grafts were anesthetized, and the right external jugular vein was removed. At 7 days after the operation, the dogs treated with the placebo (n=4) or the chymase inhibitor (n=4) were anesthetized, and then the grafted veins were removed. The concentrations of Ang II were determined with a high-sensitivity enzyme immunoassay (Peninsula Laboratories).
RNA Isolation and Northern Blot Hybridization
Total RNA was extracted from the grafted or control veins, as previously described.22 Twenty micrograms of total RNA from the grafted vein was subjected to 1% agarose gel electrophoresis and transferred to a nylon membrane.22 Each cDNA probe was labeled with 32P-dCTP by the random-primer extension method. Prehybridization and hybridization were performed according to the manufacturer’s instructions.22 The density of an individual mRNA band was normalized to that of 18S ribosomal RNA to correct for differences in RNA loading and/or transfer.
Histological Analysis
To minimize the variance of neointima formation in the grafted veins, the segment was fixed in 10% neutral buffered formalin, embedded in paraffin, and cut into sections 5 µm thick. The sections were stained with van Gieson’s elastic stain. The cross-sectional areas of intima and media were quantified with an image analysis system (VM-30, Olympus Optical Co).
Statistical Analysis
All data given in the text are expressed as mean±SEM. Statistical significance was determined with 1-way ANOVA and the Duncan multiple-range test. Differences were considered statistically significant at a value of P<0.05.
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Results |
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Enzyme Activity in the Placebo-Treated Group
The ACE activity in the grafted veins was significantly lower than that in the control veins up to 7 days after the operation (Figure 1). After 1 and 3 days in particular, the ACE activity in the grafted veins was suppressed to 5.8% and 7.7% of the control vein values, respectively. After 14 and 28 days, however, the ACE activities were significantly increased in the grafted veins. The chymase activity in the grafted veins was maintained at the same level as the control veins up to 3 days after the operation, and the chymase activities were significantly increased in the grafted veins after 7, 14, and 28 days (Figure 1).
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Expression of Growth Factor and Extracellular Matrix in the Placebo-Treated Group
Figure 2 summarizes the mRNA levels of collagen I, collagen III, fibronectin, TGF-ß1, and VEGF. The mRNA levels of collagen I, collagen III, and fibronectin in the grafted veins were not increased at 1 and 3 days after the operation. After 7 days, all the mRNA levels of collagen I, collagen III, and fibronectin were significantly increased in the grafted veins, and these levels increased gradually up to 28 days. The TGF-ß1 mRNA level in the control veins could not be quantitatively assessed, and up to 7 days after the operation, this level could not be quantified in the grafted veins. After 14 and 28 days, the TGF-ß1 mRNA levels could be detected in the grafted veins. The VEGF mRNA levels in the grafted veins were significantly increased 1 day after the operation and returned to the control level after 7 days.
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Histochemical Study of the Veins in the Placebo-Treated Group
Typical sections from the control and grafted veins 1, 3, 7, 14, and 28 days after the operation are shown in Figure 3. The ratio of intima to media of the control veins was 0.12±0.02 (Figure 4). After 7, 14, and 28 days, the ratios of the grafted veins were 0.26±0.02, 0.55±0.07, and 0.74±0.05, respectively, and the differences between the control and grafted veins were significant.
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Effect of Chymase Inhibitor in the Grafted Veins
In the chymase inhibitor–treated group, the chymase activity 7 days after the operation was 0.20±0.03 mU/mg protein, whereas in the placebo-treated group, it was 1.65±0.23 mU/mg protein (Figure 5). The chymase activity in the grafted veins treated was suppressed to 12.1% by treatment with the chymase inhibitor, but the ACE activity was not affected.
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The Ang II concentration of the control veins was below the detection limit (0.8 pg/g tissue), whereas that of Ang II concentration of the grafted veins 7 days after the operation was 33.6±5.6 pg/g tissue. The Ang II concentration of the grafted veins treated with the chymase inhibitor at 7 days decreased to below the detection limit.
The elevated mRNA levels of fibronectin, collagen I, and collagen III in the placebo-treated grafted veins were suppressed to 36.0%, 35.1%, and 35.0%, respectively, by treatment with the chymase inhibitor 7 days after the operation (Figure 6).
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The ratio of intima to media of the grafted veins in the chymase inhibitor–treated group was significantly decreased compared with that in the placebo-treated group 7 days after operation (Figure 7).
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Discussion |
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In this study, we wanted to clarify the role of the chymase-dependent Ang II–forming system on the development of vascular proliferation. The ACE activity in the grafted veins was significantly decreased up to 7 days after the operation, and in particular after 1 and 3 days, it was suppressed to <10% of the control value. The decrease in ACE activities in the acute periods is thought to be dependent on the loss of the endothelium. The arterial pressure placed on the endothelium in the grafted veins results in the loss of the endothelium, including ACE.23 Conversely, 7 days after the operation, the chymase activity was significantly increased in the grafted veins. Considering these findings, up to 7 days after the operation, the Ang II formation in the grafted veins is thought to be dependent mainly on the chymase-dependent Ang II–forming pathway. In fact, the Ang II concentration and the mRNA levels of fibronectin, collagen I, and collagen III, all of which are induced by an increase of Ang II action,7,24 were significantly increased in the grafted veins 7 days after the operation, whereas they were significantly suppressed by the chymase inhibitor. Moreover, the ratio of intima to media of the grafted veins was also decreased by the chymase inhibitor 7 days after the operation. These findings clearly demonstrated for the first time that chymase-dependent Ang II formation plays an important role in the development of vascular proliferation in grafted veins.
The characterization of a specific chymase inhibitor, Suc-Val-Pro-PheP(OPh)2, was reported by Oleksyszyn and Powers.16 The half-degradative time of the chymase inhibitor is 
20 hours in human plasma. Suc-Val-Pro-PheP(OPh)2 did not affect the activity of purified ACE and specifically inhibited chymase activity (IC50=2.8 nmol/L).25 These findings suggest that Suc-Val-Pro-PheP(OPh)2 may be a stable and strong chymase inhibitor in vivo. In fact, the inhibition by the chymase inhibitor was maintained fully up to 7 days after the operation in this study, although the inhibitor was used only during the operation and not continuously. It is reported that chymase, an enzyme that is present in mast cell granules, is released immediately from the granules on strong stimulation, binds to extracellular matrix, and continues to function for several weeks.26,27 The chymase inhibitor used in this study functions irreversibly,16 which means that the inhibitor, once bound to the enzyme, continues to inhibit it for a long time. Therefore, up to 7 days after the operation, the chymase activity was fully inhibited by treatment with the chymase inhibitor.
The accumulation of extracellular matrix is thought to cause vascular proliferation, as in the case of vessels injured by a balloon catheter.7 Ang II directly stimulates the production of extracellular matrix in cultured vascular smooth muscle cells.28 It has been unclear, however, whether the accumulation of extracellular matrix is observed in the vascular proliferation in the grafted veins. In the present study, we demonstrated an increased gene expression, as revealed by mRNA levels, for fibronectin, collagen I, and collagen III in the grafted veins from 7 to 28 days after the operation. In arteries injured by a balloon catheter, an AT1 receptor antagonist was reported to prevent the development of vascular proliferation, accompanied by suppression of the mRNA levels of fibronectin, collagen I, and collagen III.6,7 In this study, a significant suppression of the mRNA levels of fibronectin, collagen I, and collagen III was also observed in the grafted veins by treatment with the chymase inhibitor. Therefore, this extracellular matrix induced by chymase-dependent Ang II formation is thought to play a crucial role in the development of vascular proliferation in grafted veins.
In the grafted veins, the ACE activity increased significantly in comparison to the control veins 14 and 28 days after the operation. In arteries injured by a balloon catheter, upregulation of ACE was observed in the intima and was dependent on expression of ACE in macrophages and smooth muscle cells, both of which migrated to the intima.29 In this study, the increased ACE in the grafted veins may also be dependent on the expression of macrophages and smooth muscle cells. Conversely, the chymase activity increased significantly in the grafted veins 7, 14, and 28 days after the operation. Recently, chymase was reported to activate stem cell factor, which has the ability to induce accumulation of mast cells.30 In fact, the number of mast cells increased significantly in the grafted veins 14 and 28 days after the operation (M.N., unpublished observation). Therefore, the increased chymase activity is thought to be dependent on the accumulation of mast cells. We speculate as follows with regard to the mechanism of vascular proliferation by Ang II formed by ACE and chymase in grafted veins (Figure 8). ACE in the endothelium plays an important role in forming vascular Ang II in the normal state, whereas chymase is contained in mast cells and has very low enzymatic ability.31 Conversely, in the grafted veins, increased chymase activity, but not ACE activity, induces local Ang II formation and vascular proliferation in the acute phase (up to 7 days after the operation). In fact, increases of both Ang II concentration and vascular proliferation were observed in the grafted veins, but not in the chymase inhibitor–treated veins, 7 days after the operation. In the late phase (>14 days after the operation), the activation of both ACE and chymase may contribute to local Ang II formation and vascular proliferation. To determine the contribution of ACE activation to vascular proliferation in the late phase, however, further study is needed.
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TGF-ß1 is known to upregulate extracellular matrix and to contribute to neointima formation in arteries injured by a balloon catheter. Previous reports demonstrated that Ang II induces the gene expression of TGF-ß1, with the accumulation of extracellular matrix in arteries a few days after balloon injury.5–7 In the present study, the mRNA of TGF-ß1 was not detected in either the control or grafted veins up to 7 days after the operation. Conversely, the expression of TGF-ß1 in the grafted veins was detected 14 and 28 days after the operation. These findings suggest that TGF-ß1 expression is very low in control veins. Interestingly, the TGF-ß1 mRNA levels were increased in the grafted veins 14 and 28 days after the operation, but not after 7 days, when the increases of fibronectin, collagen I, and collagen III mRNAs were observed. Tazawa et al7 reported that the gene expression of extracellular matrix components was regulated by Ang II, but not by TGF-ß1. Therefore, Ang II, but not TGF-ß1, may directly induce the gene expression of extracellular matrix components in the grafted veins. Conversely, the VEGF mRNA in the grafted veins was significantly increased compared with the control veins 1 day after the operation and returned to the control level after 7 days. A previous study also reported that the VEGF mRNA of the grafted veins increased significantly 2 days after the operation and was normalized within 4 weeks.32 It was reported that overexpression of VEGF mRNA reduced vascular proliferation in the grafted veins.33 The increased level of VEGF mRNA in the acute phase after the operation, however, may be too small to prevent the development of vascular proliferation.
In conclusion, we demonstrate for the first time that chymase-dependent Ang II formation plays an important role in the development of vascular proliferation in the grafted veins and that inhibition of chymase may be useful for preventing vascular proliferation.
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Acknowledgments |
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This study was supported in part by Grant-in-Aid 12770048 for Encouragement of Young Scientists from the Ministry of Education, Science, Sports, and Culture, Japan. We thank Dr Oleksyszyn (Akoslogic Inc) for the gift of Suc-Val-Pro-PheP(OPh)2.
Received February 27, 2001; revision received May 18, 2001; accepted May 21, 2001.
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