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(Circulation. 1996;93:333-339.)
© 1996 American Heart Association, Inc.

Articles

Angiotensin II Receptor Antagonist TCV-116 Reduces Graft Coronary Artery Disease and Preserves Graft Status in a Murine Model

A Comparative Study With Captopril

Yutaka Furukawa, MD; Akira Matsumori, MD; Toshiro Hirozane, MD; Shigetake Sasayama, MD

From the Third Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, Kyoto, Japan.

Correspondence to Akira Matsumori, MD, Third Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606, Japan.

	Abstract

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Background Despite the current progress in immunosuppressive regimens, the incidence of graft coronary artery disease (CAD) after cardiac transplantation has not decreased. Recent study has revealed that angiotensin-converting enzyme (ACE) inhibition decreases CAD in rats; however, it is not clear whether this beneficial effect of ACE inhibition is due to a decrease in production of angiotensin II (Ang II) or inhibition of bradykinin degradation. To determine whether Ang II type 1 receptor (AT₁-R) blockade has an inhibitory effect on CAD, we evaluated the effects of TCV-116, an AT₁-R antagonist, in a murine model of cardiac transplantation.

Methods and Results Hearts of DBA/2 mice (H-2^d) were transplanted heterotopically to B10.D2 mice (H-2^d). Recipients were treated orally with TCV-116 (10 mg/kg per day), captopril (100 mg/kg per day), or vehicle only. Graft status, as assessed by palpation and inspection at laparotomy 70 days after transplantation, was preserved better in the TCV-116–treated group (P<.005) and in the captopril-treated group (P<.05) than in the vehicle-treated group. Intimal area in the graft coronary arterial wall decreased to 31% in the TCV-116–treated group (P<.001 versus vehicle-treated group) and to 34% (P<.005) in the captopril-treated group but was 45% in the vehicle-treated group. Fibrotic lesions of the left ventricle were less prominent in the TCV-116–treated (31%; P<.01 versus vehicle-treated group) and captopril-treated groups (33%; P<.05) than in the vehicle-treated group (54%).

Conclusions These findings show that AT₁-R blockade is at least as effective as ACE inhibition in management of chronic allograft rejection and suggest that Ang II may play an important role in chronic allograft rejection.

Key Words: transplantation • rejection • coronary disease • receptors • angiotensin

	Introduction

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Rapid progress in immunosuppressive therapeutics has remarkably improved the prevention and management of acute allograft rejection and short-term survival of cardiac transplant patients. However, as a factor limiting long-term survival, obstructive CAD remains a discouraging clinical problem for cardiac transplantation.^{1 2 3} Serial coronary angiography studies have revealed a 59% incidence of CAD at 2 years and 91% at 5 years after transplantation.^{4 5} CAD usually diffusely involves both epicardial and intramuscular arteries.^{2 6} This feature differentiates CAD from usual coronary atherosclerosis and makes it difficult to treat CAD patients by aortocoronary bypass grafting or percutaneous transluminal coronary angioplasty. Moreover, the results of retransplantation, the only definitive form of treatment for advanced CAD, are generally disappointing. The survival of retransplant patients may be as low as 40% at 2 years.^{7 8}

Recently, a consensus has been obtained that favors the existence of local renin-angiotensin systems.^{9 10 11} In addition, Ang II is thought to play an important role as a mitogen of vascular SMC in intimal hyperplasia and hypertrophy of SMC.^{12 13 14 15} Much evidence supporting the inhibitory effect of ACE inhibition on intimal hyperplasia has been reported for various nontransplant intimal hyperplasia models.^{16 17 18} Kobayashi et al¹⁹ reported that the ACE inhibitor captopril reduced CAD in a rat model. However, ACE inhibitors have also been shown to block kininase and result in accumulation of tissue bradykinin activity leading to inhibition of SMC proliferation.^{20 21 22} This is one of the reasons for the complexity of the pharmacological characteristics of ACE inhibition in SMC proliferation. Thus, at present, it is not clear whether AT₁-R blockade suppresses intimal proliferation in CAD. We therefore investigated the effects of the AT₁-R antagonist TCV-116 in comparison with those of the ACE inhibitor captopril in our murine model of CAD.

	Methods

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Experimental Model
Adult male DBA/2 (H-2^d) and B10.D2 (H-2^d) mice (7 to 9 weeks old) were obtained from the Shizuoka (Japan) Agricultural Cooperation Association and housed in stainless steel cages with controlled light/dark cycles and ad libitum access to food and water.

DBA/2 mice served as transplant donors and B10.D2 mice as recipients. These two strains are MHC-antigen compatible but differ in non-MHC antigens, and the transplanted donor hearts display intimal hyperplasia in the coronary arteries, together with interstitial and perivascular fibrosis in the chronic stage.²³ Heterotopic cardiac transplantation was performed as previously described.²⁴ In brief, donors and recipients were anesthetized with 4% chloral hydrate (0.01 mL/g body weight IP) before surgery. Donor hearts were perfused with chilled, heparinized saline via the inferior vena cava and harvested after ligation of the vena cava and pulmonary veins. The aorta and pulmonary artery of donor hearts were anastomosed to the abdominal aorta and inferior vena cava of recipients by use of a microsurgical technique. Ischemic time was routinely 40 to 60 minutes, and the success rate was approximately 90%. Mice with technical failures within the first 72 hours of transplantation were excluded from experiments. Viability of the cardiac allograft was assessed by daily abdominal palpation and confirmed by ECG. The day of rejection was defined as the day of cessation of heartbeat.

Drug Preparation and Treatment
TCV-116 was synthesized by Takeda Chemical Industries, Ltd. Since TCV-116 is insoluble in water, it was suspended in 5% gum arabic. Captopril was dissolved in distilled water. Allogeneic recipient mice were orally administered TCV-116 (10 mg/kg per day), captopril (100 mg/kg per day), or vehicle (5% gum arabic) alone. Doses of the drugs were determined by the results of our previous studies with a murine myocarditis model^{25 26} and experiments in rats,^{19 27} with consideration given to the difference between species.²⁸

Evaluation of Graft Status
Surviving mice were examined by graft palpation and anesthetized by inhalation of diethyl ether, and the color of the beating grafts was observed microscopically in a low-power field. Functional status of the graft was scored by judging the cardiac impulse by abdominal palpation and was assessed on a scale of 0 to 4, with 4 representing a normal heartbeat and 0 representing the absence of mechanical activity, as previously described.²⁵ Color of the graft was graded as follows: 0, completely (>90%) dark-yellowish white; 1, more dark-yellowish white than pink; 2, less dark-yellowish white than pink or equally pink; 3, completely (>90%) pink. The sum of the functional score and the score for color was defined as the overall graft status score. The score used was the average of those obtained in a blinded manner by two observers.

Histological Examination
Mice were killed 70 days after transplantation for morphometric analyses of neointima and fibrotic lesions of left ventricle. In addition, to study the time course of chronic rejection, including CAD, mice were killed 7, 14, or 28 days after transplantation. Grafts were sectioned transversely at the maximal circumference of the ventricle and fixed in 10% formalin. Tissues were embedded in paraffin and stained with hematoxylin and eosin, Masson's trichrome, and elastic van Gieson.

Morphometry of Neointima and Fibrotic Lesions of Left Ventricle
As we previously described,²³ the number of points that lay over the intima or media was counted with use of an eyepiece grid with 100 points, and the areas of the respective parts were calculated with use of the formula 0.01xnumber of pointsxgrid area. Sections stained with elastic van Gieson were examined, and intimal area (%) was defined as

For morphometric examination of fibrotic lesions, sections stained with Masson's trichrome were used. As in morphometry of neointima, the number of points that lay over the left ventricular myocardium or the interstitial fibrosis (which includes subsequent fibrosis after necrosis) and perivascular fibrosis of the left ventricular myocardium were counted with use of an eyepiece grid with 100 points. The areas of the respective parts were calculated by the formula 0.01xnumber of pointsxgrid area. The area of fibrotic lesions (%) was defined as

Statistical Analysis
The Mann-Whitney U test was used to compare allograft survival time or graft status scores between groups, since these data were nonparametrically distributed. Findings for percent intimal area and percent fibrotic lesion were compared by use of one-way ANOVA followed by Fisher's protected least significant difference. Values of P<.05 were considered significant.

	Results

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Graft Survival
All recipient mice appeared healthy throughout the study period. The percent survival of DBA/2B10.D2 allografts and DBA/2 syngrafts is shown in Fig 1. All DBA/2 syngrafts survived for 70 days. In the vehicle-treated group, 7 (70%) of 10 allografts survived. Treatment with TCV-116 or captopril tended to improve survival, to 90% (9 of 10 allografts) and 80% (8 of 10 allografts), respectively. There were, however, no statistically significant differences in graft survival between any two allograft groups.

View larger version (16K): [in this window] [in a new window]   Figure 1. Plots indicate survival of murine cardiac grafts. All of the DBA/2 syngrafts survived for 70 days, whereas 70% (7) of 10 vehicle-treated DBA/2B10.D2 allografts survived for 70 days. Treatment with TCV-116 (10 mg/kg per day) improved survival rate to 90% (9 of 10) and treatment with captopril (100 mg/kg per day) improved survival rate to 80% (8 of 10). However, there were no significant differences in graft survival among the three allograft groups.

Graft Status of Grafts That Survived for 70 Days
All syngrafts survived for 70 days and for each graft, status remained excellent. As shown in Table 1, graft status was considerably poorer in the vehicle-treated group 70 days after transplantation (graft status score, 3.57±1.27; mean±SD). Treatment with TCV-116 maintained the graft status of most allografts, and mean graft status score was 5.56±0.88 (P<.01 versus vehicle-treated group). Captopril also tended to maintain good graft status (graft status score, 5.00±1.41). However, there were no statistically significant differences between the graft status scores of captopril-treated and vehicle-treated groups.

View this table: [in this window] [in a new window]   Table 1. Graft Status of Allografts That Survived for 70 Days

Histological Findings
Sections of allografts harvested 7 days after transplantation exhibited mononuclear cell attachment to the endothelium of coronary arteries and mild perivascular/interstitial infiltration, whereas syngrafts did not exhibit these features that are suggestive of acute rejection. However, there was no intimal thickening in either allografts or syngrafts (Fig 2A, 2B, and 2C). Allografts harvested 14 days after transplantation exhibited more prominent vasculitis and evidence of cellular rejection, such as irregular luminal surfaces suggestive of endothelial edema, more mononuclear cell attachment and infiltration, and mild intimal thickening (Table 2) in most of their coronary arteries (Fig 2D and 2E). Although inflammatory changes caused by acute rejection had declined in allografts by 28 days after transplantation, advanced intimal thickening was observed in the coronary arteries (Fig 2F), and most coronary arteries exhibited CAD at this stage. All of these pathological findings also were observed in allografts treated with TCV-116 or captopril with a similar time course but were less prominent. Thereafter, CAD progressed more slowly until 70 days after transplantation (Fig 3A), involving both large and small arteries, as in human CAD (Fig 3B). Coronary arteries of DBA/2 syngrafts remained almost intact 70 days after transplantation (Fig 3D). Treatment with TCV-116 (Fig 3C) and with captopril each ameliorated intimal thickening in allografts surviving at 70 days. Advanced perivascular and interstitial fibrosis were also observed in vehicle-treated allografts surviving at 70 days (Fig 3E). Treatment with TCV-116 (Fig 3F) and captopril each reduced the severity of these histopathological findings.

View larger version (216K): [in this window] [in a new window]   Figure 2. Tissue sections of mouse cardiac allografts and syngrafts. A, Section of an allograft treated with control vehicle 7 days after transplantation. Attachment of accumulated mononuclear cells to the endothelium and mild perivascular/interstitial infiltration are demonstrated (hematoxylin-eosin stain, magnification x360). B, Same section as in Fig 2A. No intimal thickening is present in the coronary artery (elastic van Gieson stain, magnification x360). C, Section of a 7-day-old DBA/2 syngraft. There is only slight cellular infiltration, no intimal thickening, and no mononuclear cell attachment to the endothelium (hematoxylin-eosin stain, magnification x360). D, Section of a 14-day-old allograft treated with control vehicle. Features of acute vasculitis were present, including prominent mononuclear cell attachment to the endothelium, perivascular/interstitial infiltration, and irregular luminal surfaces (hematoxylin-eosin stain, magnification x360). E, Same artery as in Fig 2D. Mild intimal thickening including attached mononuclear cells is present. F, Section of a 28-day-old allograft treated with control vehicle. Fibrocellular intimal thickening is advanced in comparison with that in 14-day-old allografts, whereas acute inflammatory changes are less pronounced (elastic van Gieson stain, magnification x360). Bar=50 µm.

View this table: [in this window] [in a new window]   Table 2. Progression of Arterial Lesions in Grafts1

View larger version (219K): [in this window] [in a new window]   Figure 3. Tissue sections of mouse cardiac allografts and a syngraft that survived for 70 days. A, Section of a vehicle-treated allograft exhibited progression of CAD (elastic van Gieson stain, magnification x360). B, Same section as in Fig 3A. Intimal hyperplasia involves both large and small arteries (elastic van Gieson stain, magnification x180). C, Section of a TCV-116–treated allograft (elastic van Gieson stain, magnification x360). Progression of CAD was less prominent in the group treated with TCV-116 (10 mg/kg per day) than in the vehicle-treated group. D, Section of a DBA/2 syngraft. There is no intimal hyperplasia in the coronary artery (elastic van Gieson stain, magnification x360). E, Section of a vehicle-treated allograft. Progressive perivascular and interstitial fibrotic lesions are noted (Masson's trichrome stain, magnification x180). F, Section of an allograft treated with TCV-116. Fibrotic lesions were less prominent than in vehicle-treated allografts (Masson's trichrome stain, magnification x180). Bar=50 µm.

Morphometric Examination of Intimal Hyperplasia
Intimal thickening of coronary arteries in grafts was confirmed by point counting. No detectable intimal thickening was noted in any graft harvested 7 days after transplantation. Intimal thickening appeared in allografts harvested 14 days after transplantation but may have included attached mononuclear cells and endothelial edema. By 28 days after transplantation, these findings of acute inflammation were less prominent, and progression of intimal thickening of coronary arteries in allografts was suppressed in the groups treated with TCV-116 or captopril. Thereafter, intimal thickening progressed, especially in vehicle-treated allografts, to 70 days after transplantation (Table 2). Overall, in vehicle-treated allografts, the intima comprised 45.2±7.6% (mean±SD, n=7) of the coronary arterial walls, whereas in DBA/2 syngrafts, the intima comprised 12.3±2.3% of coronary arterial walls (n=10). TCV-116 and captopril treatment each significantly reduced percent intimal areas, to 31.2±8.2% (n=9, P<.001 versus vehicle-treated) and 33.7±7.0% (n=8, P<.005 versus vehicle-treated; ANOVA), respectively (Fig 4).

View larger version (55K): [in this window] [in a new window]   Figure 4. Columns in bar graph indicate percent intimal area of mouse cardiac grafts. Vehicle-treated allografts (n=7), TCV-116–treated allografts (n=9), captopril-treated allografts (n=8), and DBA/2 syngrafts (n=10) were harvested 70 days after transplantation. Sections stained with elastic van Gieson were examined. The percent intimal area of a graft was defined as the average value of the percent intimal areas obtained by examining 7 to 14 sections of the coronary arteries in the graft, as described in the text. Each column represents the mean±SD of the percent intimal area calculated for all allografts or syngrafts. *P<.005 vs vehicle-treated allografts. **P<.001 by one-way ANOVA.

Morphometric Examination of Interstitial and Perivascular Fibrosis
As shown in Fig 5, interstitial and perivascular fibrotic lesions occupied 53.9±6.9% (mean±SEM) of the left ventricle in vehicle-treated allografts but only 13.9±2.2% of the left ventricle in DBA/2 syngrafts. TCV-116 and captopril each reduced the percent fibrotic lesion, to 31.2±5.4% (P<.01 versus vehicle-treated) and 33.3±7.2% (P<.05 versus vehicle-treated; ANOVA), respectively.

View larger version (51K): [in this window] [in a new window]   Figure 5. Columns in bar graph indicate percent fibrotic area of mouse cardiac grafts. Vehicle-treated allografts (n=7), TCV-116–treated allografts (n=9), captopril-treated allografts (n=8), and DBA/2 syngrafts (n=10) were harvested 70 days after transplantation. Sections stained with Masson's trichrome were examined. The percent fibrotic area of a graft was defined as a percentage of the left ventricular wall area of the graft, as described in the text. Each column represents the mean±SEM of the percent fibrotic area calculated for all allografts or syngrafts. *P<.05 vs vehicle-treated allografts. **P<.01 by one-way ANOVA.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In the present study, we showed that DBA/2B10.D2 cardiac allografts with long-term survival without any immunosuppression developed arterial lesions that were similar to those of human CAD and previous animal models of CAD.^{2 6 29 30 31} We demonstrated that oral administration of TCV-116 (10 mg/kg per day) and captopril (100 mg/kg per day) each inhibited intimal hyperplasia in CAD in a murine model.

Human CAD has some histopathological features that distinguish it from ordinary atherosclerosis, including diffuse distribution, concentric narrowing, rare foci of calcification or atheromatous plaque, and often an intact elastic lamina.^{2 6} On the other hand, it appears to share histopathological features with late restenosis after coronary angioplasty, demonstrating fibrocellular proliferation of macrophages and vascular SMC in the neointima.^{32 33} These findings suggest that the presence of a repair process after vascular injury, which is common to these conditions, may explain their common histopathological features, although the initial injury differs.

One of the initial vascular injuries leading to CAD has been hypothesized to be an immunologic injury or activation of the endothelium followed by activation and infiltration of mononuclear cells, formation of thrombus, activation of various growth factors and cytokines, and SMC migration and proliferation.^{34 35} The development and progression of CAD appears to be an excessive response during a multifactorial repair process of this kind. There may be two approaches to the treatment of CAD: (1) prevention of the initial vascular injury by immunosuppression, and (2) modulation of the repair process, including intimal hyperplasia of SMC.

Ang II, as one of the potent mitogens of SMC, and the vascular renin-angiotensin system have attracted considerable research attention.^{9 10 11 12 13 15 36} Ang II can stimulate both hypertrophy and proliferation, depending on the balance of growth factors such as transforming growth factor-ß, basic fibroblast growth factor, and platelet-derived growth factor.^{10 13 14} Consequently, the preventive effects of ACE inhibitors and AT₁-R antagonists on restenosis after balloon injury have been examined in animal models.^{16 17 18 21 37} Farhy et al²¹ compared the effects of the ACE inhibitor ramipril with the AT₁-R antagonist losartan and found that ACE inhibition was more effective than AT₁-R blockade in preventing restenosis and that this difference might be due to inhibition of kininase and accumulation of kinins. However, another recent study³⁷ demonstrated that the AT₁-R antagonist TCV-116 was as effective in inhibiting neointimal hyperplasia as the ACE inhibitor cilazapril in a rat carotid artery injury model, and it remains controversial which of these treatments is more effective in preventing restenosis. ACE inhibition also was reported to be effective in inhibiting the progression of CAD in a rat model.¹⁹ However, it has not been clarified whether AT₁-R blockade is effective in preventing CAD in animal models.

Our findings demonstrated that AT₁-R blockade was as effective as ACE inhibition in preventing CAD and suggest the importance of Ang II in the progression of CAD. An ACE-independent pathway mediated by chymase recently has been reported to be a local source of Ang II.³⁸ In humans, considerable chymase-like activity is detectable in coronary arteries and can be a local source of Ang II in coronary arteries.³⁹ Some investigators contend the presence of chymase is one of the reasons clinical trials for the prevention of restenosis have failed,^{40 41} in addition to the use of smaller doses of drugs than used in animal experiments. Considering the beneficial effects of AT₁-R blockade in our murine CAD model and the existence of an ACE-independent pathway in the human coronary artery as a local source of Ang II, AT₁-R blockade may have some beneficial effects in treatment of CAD.

Another important role of AT₁-R blockade is immunomodulation. Clinical studies of CAD revealed an association between occurrence of major rejection episodes and development of CAD.^{3 4} Accordingly, early rejection episodes appear to influence late CAD. Possible immunoregulatory effects of Ang II, such as T-cell chemotaxis, have been reported,^{42 43} and it has been hypothesized that in some diseases, such as sarcoidosis, Ang II may play a role in inflammatory processes. We recently found that TCV-116 improved histopathological findings in a murine model of acute viral myocarditis,²⁵ and in the present study, TCV-116 also appeared to reduce inflammatory changes in 7-day-old and 14-day-old allografts. However, we obtained findings indicative of acute vasculitis (Fig 2D) in all 14-day-old allografts, regardless of treatment. This suggests the importance of modification of the repair process after vasculitis rather than reducing acute inflammation in AT₁-R blockade and ACE inhibition in prevention of CAD.

The histopathological findings in allografts with long-term survival were significantly improved in the TCV-116–treated group. This may have been principally the result of inhibition of CAD. However, direct inhibitory effects of TCV-116 on the development of fibrosis also might have been responsible in part, since Ang II stimulates fibroblast proliferation and collagen synthesis in the interstitium via the AT₁-R.^{44 45 46} Recent studies have revealed the beneficial effects of TCV-116 on cardiac tissue remodeling, including reduced fibrosis. Kojima et al²⁷ reported that treatment with TCV-116 reduced the extent of left ventricular fibrosis and collagen accumulation in spontaneously hypertensive rats. Considering these findings and our own for murine myocarditis,²⁵ the attenuation of tissue remodeling after inflammation induced by acute cellular rejection might also be an important reason for histological improvement.

In conclusion, the present study demonstrated that AT₁-R blockade significantly inhibited the progression of CAD in allografts that survived long-term and preserved graft status in a murine model of CAD. These beneficial effects were at least equivalent to those of ACE inhibition with captopril. Given the existence of chymase—an ACE-independent source of Ang II—in humans, AT₁-R blockade may prove useful therapeutically for inhibition of CAD. Further studies are necessary to clarify how AT₁-R blockade inhibits the progression of CAD as a manifestation of chronic allograft rejection.

	Selected Abbreviations and Acronyms

 

ACE = angiotensin-converting enzyme Ang II = angiotensin II AT1-R = angiotensin II type 1 receptor CAD = graft coronary artery disease MHC = major histocompatibility antigen SMC = smooth muscle cells

	Acknowledgments

 
This work was supported by a research grant from the Ministry of Health and Welfare and by a grant-in-aid for developmental scientific research and for general scientific research from the Japanese Ministry of Education, Science, and Culture. We thank Takeda Chemical Industries, Ltd for supplying TCV-116.

Received April 18, 1995; revision received July 11, 1995; accepted August 29, 1995.

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