© 1995 American Heart Association, Inc.
Articles |
Mechanism of Inhibition of Neointimal Formation by the Angiotensin-Converting Enzyme Inhibitor Cilazapril
A Study in Balloon Catheter–Injured Rat Carotid Arteries
From the Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Correspondence to Jürgen Fingerle, Pharma Division, Preclinical Research, PRPV, F. Hoffmann-La Roche Ltd, CH-4002 Basel, Switzerland.
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Abstract |
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Abstract We investigated the mechanism of inhibition of neointima formation by the angiotensin-converting enzyme inhibitor cilazapril in a rat model of balloon-catheter injury in the carotid artery. We looked for the effects of cilazapril on all phases of the response to injury, ie, on proliferation of smooth muscle cells (SMCs) in the media, their migration, their proliferation in the neointima, and their deposition of extracellular matrix in the neointima. Although treatment was discontinued after 2 weeks, the inhibitory effect of cilazapril on neointimal formation was evident even 52 weeks after injury. The amount of extracellular matrix deposited in the intima during cilazapril treatment was decreased by 20% 2 weeks after injury, but no effect was seen if tissues were analyzed at 4 or 52 weeks. [3H]Thymidine-labeled cells (pulse labeling as well as 14-day continuous labeling) showed a decrease in SMC labeling in the tunica media by 50%, but no inhibition in the labeling indices was seen in the neointima. The fraction of unlabeled neointimal cells in the cilazapril-treated rats as judged from continuous labeling experiments was inhibited by 86%. Taken together, these data suggest an antiproliferative effect on medial SMCs and an inhibition of SMC migration into the intima by cilazapril. Since intimal extracellular matrix deposition was only delayed, the decrease in medial SMC proliferation and subsequent migration seems to be the main reason for the reduction of neointima formation.
Key Words: rat • smooth muscle cell • proliferation • migration • cilazapril
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Cilazapril is the first ACE inhibitor shown to inhibit intimal thickening after balloon-catheter injury in rats.1 The phenomenon has been reproduced with other ACE inhibitors2 3 4 and other animal models of intimal hyperplastic diseases (eg, vein graft hyperplasia in rats5 and rabbits6 and allograft hyperplasia in rats7 ). The underlying mechanisms, however, are still unclear. In balloon catheter–injured guinea pigs cilazapril is effective,8 but in other animal species such as swine9 10 or nonhuman primates11 little or no efficacy has been demonstrated. A retrospective study on the efficacy of ACE inhibitors on restenosis in humans suggests a beneficial effect12 ; in contrast, a prospective randomized trial with cilazapril was negative.13 These species differences prompted us to further analyze the mechanisms underlying the inhibition of intimal thickening after balloon-catheter injury by cilazapril.
The sequence of events leading to intimal thickening after balloon-catheter injury in the rat is well documented. SMCs proliferate in the media14 15 ; after 2 to 7 days the SMCs migrate into the intima, after which they start a transient phase of proliferation that lasts about 2 weeks.15 Finally, for about 4 weeks they continue to deposit large amounts of ECM material.16 Little data are available on the effect of ACE inhibitors on the proliferation of SMCs in vivo. Prescott et al4 reported no inhibition of proliferation in the tunica media after balloon-catheter injury in the rat by the ACE inhibitor benazeprilate. Capron et al2 showed a small but insignificant decrease with ramipril. Both studies suggest that inhibition of ACE caused inhibition of migration of SMCs into the intima. We focused on the effect of cilazapril on all four phases of SMC activation after balloon-catheter injury to the rat. We show that cilazapril inhibits incorporation of thymidine into medial but not intimal SMCs. ECM deposition was inhibited only slightly and transiently, and we conclude that a main mechanism of inhibition of neointimal formation by cilazapril is inhibition of SMC migration from the media into the intima.
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Methods |
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Carotid Artery Injury
Male Wistar Kyoto rats (300 to 400 g) were obtained from BRL. The animals were anesthetized with sodium pentobarbital 40 mg/kg IP (Vetanarcol, Veterinaria). The left carotid artery was exposed at the bifurcation, and a 2F embolectomy catheter was inserted.1 16 The inflated balloon was pulled through the common carotid artery three times. After permanent ligation of the external carotid artery the wound was closed, and the animals were kept in pairs and fed commercial chow and water ad libitum.
Drug Administration
Cilazapril was administered as a food admixture starting 6 days
before surgery.1 During the first and second day after
ballooning cilazapril was administered by gavage (10 mg/kg) to ensure
uptake. On the basis of a food consumption of 20 g per rat per day, 200
mg cilazapril was mixed with 1 kg rat chow to give a daily supply of
10 mg cilazapril per kg body wt. Food consumption by the
experimental animals was controlled every other day.
DNA Synthesis In Vivo
Cellular proliferation in vivo was assessed by using
[3H]thymidine labeling. Two protocols were used. To
estimate the proliferation rate per day, exactly 1.85x107
Bq/kg tritiated thymidine (2.5x1011
Bq · mmol-1 · L-1,
3.7x107 Bq/mL; New England Nuclear) was injected
intraperitoneally at 17 hours, 9 hours, and 1 hour
before death.15 To determine the cumulative proliferation
rate over the first 2 weeks after injury, an osmotic minipump with a
volume of 2 mL (2ML2 Alzet) filled with 7.4x107 Bq
[3H]thymidine (2.5x1011
Bq · mmol-1 · L-1,
3.7x107 Bq/mL) was implanted in the peritoneum at the time
of arterial injury.
Labeled nuclei were detected by autoradiography on perfusion-fixed cross-sections (see below) that were dipped in Kodak NTB2 emulsion and developed after 2 weeks at 4°C. The thymidine index was expressed as (labeled nuclei/total nuclei)x100.
Morphometry
Prior to perfusion fixation (2.5%
glutaraldehyde in 0.1 mol/L cacodylate buffer, pH 7.4,
for 15 minutes at 90 mm Hg), the rat was deeply anesthetized
with pentobarbital 150 mg/kg IP. The abdomen was opened, and the rat
was killed by further intravenous injection of
pentobarbital. The chest was quickly opened, and a gavage cannula (No.
20) was inserted into the aorta via the left ventricle. Blood was
flushed out with phosphate-buffered saline before fixation was
started. The vessels were carefully removed and fixed further by
immersion in the same solution for 90 minutes at 4°C, cut into six
equal segments (6 mm long), and subjected to epoxy resin embedding
(Epon 812). Semithin sections were cut from the central segments (12
and 18 mm distal from the aortic origin of the carotid artery) and
stained with toluidine blue and basic fuchsin.17
Cross-sectional areas of vessel wall tissues were determined by
using a computer-aided morphometry system (Diasys II; Heinz Meyer,
DataLab).
Electron Microscopy
For transmission electron microscopy (Philips CM12/STEM), the
perfusion-fixed and embedded material described above was used.
After immersion fixation, the center segments of the arteries were
rinsed overnight in 0.1 mol/L cacodylate buffer and 7% sucrose, pH
7.4, at 4°C. Sodium permanganate (0.05%) in cacodylate buffer, pH
7.4, was used for postfixation at 4°C for 60 minutes. After
dehydration with ethanol and propylene oxide and embedding in epoxy
resin, ultrathin sections were cut and stained with uranyl acetate and
lead citrate.
Determination of the Amount of ECM
The relative area occupied by ECM versus cellular bodies was
determined on cross sections at 14, 28, and 365 days after
balloon-catheter injury by using the point-hit
method.18 A total of 12 transmission electron micrographs
(x6000) were taken from each cross section such that the micrographs
covered the entire thickness of the intima.16 One hundred
thirty test points over each micrograph were analyzed by using
a video camera and a semiautomatic computer-driven morphometry
system (DIASYS II). The number of test points covered by
ECM was expressed as the percent of total test points.
Statistical Analysis
Treatment effects on cross-sectional areas were
analyzed by using the Kruskal-Wallis test (PROC
NPAR1WAY, SAS). In the case of
overall significance (P<.05), treatment effects on separate
days were compared by using the Wilcoxon test. Treatment
effects on proliferative activity and absolute number of nuclei were
analyzed by two-way ANOVA by using the factors
"treatment" and "time" and their interaction (PROC
GLM, SAS). In the case of overall significance
(P<.05), treatment effects on separate days were compared
by using the least-squares mean from an ANOVA with treatment nested
in time.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Neointima Formation
From our morphometry data (Fig 1
),
it was evident that cells appeared in the intima 5 days after
balloon-catheter injury, and substantial thickening was seen after
9 days. Neointimal thickening during the first 2 weeks
after injury was inhibited in the cilazapril-treated rats by
81%1 as judged from neointimal
cross-sectional areas (Fig 1). If the number of
nuclear profiles per cross section was used as a crude measure of
intimal cellularity, in cilazapril-treated rats a reduction of 76%
was evident (Table 1). On the basis of
these data, we wanted to know whether cilazapril delays or actually
inhibits neointimal thickening. When rats were treated
continuously with cilazapril for 52 weeks (Fig 2), neointima formation was
inhibited by 75%. When the drug was discontinued 2 or 4 weeks after
balloon injury and the rats were analyzed after 52 weeks, the
neointima was still reduced (40% if cilazapril was
administered for 2 weeks and 57% for 4 weeks; Fig 2).
These results suggest that cilazapril inhibits neointimal
size mainly through events atanearlystageaftervessel-wall
injury.
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)- and placebo (
)-treated rats. At 6, 7, 9,
and 14 days the neointimal area was reduced
(P<.05) in the cilazapril-treated rats. Values are
mean±SEM; 8<n<24 (two sections per rat were measured).
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Thymidine Labeling
In placebo-treated rats the peak of medial thymidine
labeling was observed 4 days after injury (Fig 3,
top). Cilazapril-treated rats showed labeling
indices in medial SMCs, which were significantly reduced
(P=.0001 by two-way ANOVA). A maximum inhibition (45%)
was reached at day 4 after injury. In the intima, however, no
significant difference in maximum labeling indices could be seen
between the two experimental groups (Fig 3, bottom). In
some rats tritiated thymidine was infused continuously during the
entire observation period (0 to 14 days after balloon-catheter
injury). The results from the pulse-labeling experiment could be
substantiated, as overall labeling in the media was reduced by 50% in
cilazapril-treated rats, whereas no difference between the
two groups of rats was evident in the intima (Table 2).
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The proliferative response of medial SMCs is thought to reflect the replacement of those SMCs that are destroyed by balloon-catheter injury. The density of nuclear profiles in the tunica media in both groups increased significantly (P<.0001 by ANOVA) between 2 and 14 days after injury by a factor of 2.4 in the placebo-treated rats (from 839±192 nuclei per millimeter-squared at day 2 to 2040±118 nuclei per millimeter-squared at day 14) and by a factor of 1.6 in cilazapril-treated rats (from 1169±155 nuclei per millimeter-squared at day 2 to 1895±141 nuclei per millimeter-squared at day 14). Whereas the increase in nuclear density was significantly smaller in cilazapril-treated rats (P<.05), the final nuclear density at day 14 did not differ significantly between the two groups.
Calculation of the Fraction of Unlabeled
Neointimal Cells
From our data we have no indication of an inhibition of
neointimal cell proliferation after cilazapril treatment.
This raises the question of whether ACE inhibition could inhibit SMC
migration. From our continuous thymidine-labeling experiments we
could determine which cells in the neointima never took up
the label. These unlabeled cells were most probably derived from the
tunica media via migration through the internal elastic lamina without
entering S phase throughout the experiment. Thus, they could be used as
a marker for cellular migration. The results of this experiment are
summarized in Table 3. The neointimal cell
number in cilazapril-treated rats 2 weeks after injury was reduced
by 75%. In these tissues the reduction of unlabeled
neointimal cell numbers was in the same order of magnitude
(85%). The most likely explanation for this profound reduction in the
number of unlabeled cells is the inhibition of SMC migration from the
tunica media into the intima during cilazapril treatment.
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ECM Volume
More than half the neointimal volume in the
balloon catheter–injured rat carotid artery is occupied by
ECM.16 We wanted to know, therefore, whether cilazapril
would reduce the volume fraction of ECM in the neointima.
We examined the cross-sectional area occupied by extracellular
material in the tunica intima for up to 52 weeks after injury in
placebo- and cilazapril-treated rats (Fig 4). Despite a significant reduction of
total neointimal size after cilazapril treatment (Fig 2
), no long-term (up to 52 weeks) change in the
intimal extracellular volume fraction was evident. Two weeks after
injury, however, the matrix was reduced by 20% in the
cilazapril-treated group. From these data it was clear that a delay
of ECM deposition could contribute to the reduced
neointimal size 2 weeks after injury but that no
long-term changes could be expected.
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Discussion |
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Our data clearly show that cilazapril inhibited medial SMC proliferation in balloon catheter–injured rat carotid arteries. In contrast, intimal SMC proliferation was not inhibited by the drug. The amount of ECM in the intima was normal, but the time course of deposition was delayed. Our data further suggest that the inhibition of migration of SMCs from the intima to the media was a main cause for the inhibitory effect of cilazapril on overall intimal thickening.
We analyzed the total intimal cross-sectional area as well as the relative amount of intimal ECM for up to 52 weeks after injury. While we found a persistent reduction of neointimal cross-sectional area during cilazapril treatment in the range of 80%, we detected no effect of cilazapril on ECM deposition except at the 2-week point, when a 20% reduction was evident.
From these data we reasoned that cilazapril exerts its inhibitory activity by affecting intimal SMC number or size rather than ECM. This interpretation could be substantiated since the actual number of nuclei per cross section was reduced in parallel with the reduction in total neointimal cross-sectional area. When overall neointimal size was analyzed for up to 52 weeks after injury, cilazapril maintained its inhibitory effect despite discontinuation of drug treatment after 2 or 4 weeks. Discontinuation of drug treatment after 2 rather than 4 weeks caused a significantly smaller inhibition of neointimal thickening 52 weeks after injury, implying that processes are affected that extend for more than 2 weeks. Nevertheless, this suggests that ACE inhibition permanently reduces the cellular content of the neointima via a mechanism that is active during an early stage of neointimal development. These data can be interpreted to indicate that cilazapril affected those cells that initially populate the neointima by inhibiting either medial SMC proliferation or migration. Alternatively, the proliferative activity of the intimal cells could have been lowered by cilazapril. Using two different labeling protocols (pulse labeling for 24 hours and continuous labeling from the time of injury until death at day 14), we found no evidence for a decrease in labeling indices in intimal cells in cilazapril-treated rats, strongly suggesting that proliferation of these cells is not inhibited by the drug. No data are available yet to relate this finding to other ACE inhibitors. Despite this lack of efficacy of cilazapril, Ang II is shown to increase intimal proliferation in a similar model19 if given in pharmacological doses. Several studies suggest that ACE inhibition effects are mediated via the Ang II receptor 1 (AT1) pathway.4 20 21 AT1 receptors are predominantly present in the neointima,22 but AT2 receptors have also been detected.23 Our results could be interpreted such that either the reduction of Ang II in the neointima after ACE inhibition was insufficient, as discussed by Dzau24 and Dzau and Pratt,25 or that endogenous Ang II does not drive neointimal proliferation.
The reduction in neointimal formation is seen only at high doses of cilazapril (>3 mg · kg-1 · d-1; data not shown). It has been shown for other ACE inhibitors at similar doses that besides inhibition of Ang II, increased kinins and nitric oxide contribute to the inhibition of neointimal formation.26 27 It was not the subject of this study to elucidate the pharmacology of ACE inhibition. We can clearly show, however, that even at high doses ACE inhibition fails to inhibit intimal SMC proliferation.
As far as medial SMCs are concerned, inhibition of Ang II receptors in vivo reduces proliferation,4 and administration of Ang II in pharmacological doses increases medial proliferation,19 suggesting a direct role of Ang II in the process. When we looked for proliferative activity in the tunica media, a significant reduction by drug treatment was revealed by two-way ANOVA. Such an inhibitory effect was not described for other ACE inhibitors but may have been missed in studies using benazeprilate4 or ramipril2 due to the smaller sample sizes. Evidence suggests that bFGF is the main mitogen for medial SMC proliferation; bFGF is released from injured SMCs and acts in a paracrine fashion on neighboring intact SMCs.28 There is no evidence that bFGF is also an endogenous mitogen for intimal SMC proliferation, since an antibody that inhibits SMCs in the media failed to inhibit proliferation in the intima.29 Since cilazapril has a selective efficacy for the reduction of medial SMC proliferation, the bFGF pathway may be linked to ACE, as recently suggested by Fishel et al,30 who report an induction of ACE in cultured SMCs by bFGF.
One way to explain the apparent paradox that cilazapril inhibits intimal thickening without affecting intimal proliferation is to postulate that cilazapril inhibits SMC migration from the media into the intima. From our continuous thymidine-labeling experiments we were able to estimate the number of nonproliferative cells in the neointima. From our calculation we can conclude that the appearance of cells in the neointima that never took up thymidine is inhibited by cilazapril by 85%. Labeled cells from the same tissues were inhibited to a similar extent (75%). This clearly shows that cilazapril not only affects medial cells in a proliferative but also in a nonproliferative stage.
Since migration of both proliferative as well as nonproliferative cells was affected, we have no indication that a subpopulation of SMCs is a target of ACE inhibitors. However, as the diversity of SMCs in terms of ontogenic origin,31 proliferative behavior,32 33 and ACE activity34 is well known, we cannot exclude that a subpopulation of cells is prone to ACE inhibition.
In contrast to SMC proliferation, we know little about SMC migration, nor do we have a direct marker for this process. Indirect evidence has therefore been used to describe SMC migration in vivo.4 The observation of nonproliferating cells in the neointima prompted Clowes and Schwartz35 to propose the concept that SMC migration must occur to initiate neointimal thickening. They calculated that the number of migrating cells that do not proliferate is the same as the number of cells that show proliferative activity.
It is also possible that the extent of migration of medial SMCs is a direct consequence of proliferation in the media; hence, the reduction of neointimal thickening could also be directly related to reduced medial proliferation. Since cytokines can induce processes linked to migration as well as proliferation, it is difficult to separate the two. The question arises of whether the inhibition of medial SMC proliferation in cilazapril-treated rats may contribute to the reduced neointimal thickening. We may postulate that a certain level of cellular density must be reached in the injured media before migration can occur. A reduced proliferation in the media in cilazapril-treated rats may therefore directly explain the reduced migration.
The failure of ACE inhibition in several animal species such as pigs and monkeys9 10 11 to affect neointima formation can be explained by species differences, eg, the presence or absence of ACE-bypassing enzymes such as chymase.36 37 The very high dose of ACE inhibitor used in rats certainly limits the possibility to extrapolate the data to other species. The finding that cilazapril fails to inhibit intimal SMC proliferation even at high concentrations could suggest, however, that in those arteries in which SMCs exist in the intima before drug treatment there is no efficacy in reducing neointima formation after balloon-catheter intervention. Intimal SMCs are found in most large arteries and in particular in diseased human coronary arteries subjected to angioplasty.
In summary, we provide evidence that the ACE inhibitor cilazapril inhibits medial SMC proliferation in injured rat carotid arteries. The number of nonproliferating cells in the neointima was also reduced, suggesting an inhibitory effect on SMC migration. Whereas medial SMC proliferation was inhibited, no effects on intimal SMC proliferation or long-term ECM deposition were observed. This could predict a low efficacy of ACE inhibitors in injury models with preexisting intimal SMCs in which migration may play a subordinate role.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We thank Christine Michael, Käthi Schietinger, Feridun Schodjai, Georges Wdonwicki, and Philippe Wyss for excellent technical assistance and Dr L. Banken for his advice and help in handling statistics.
Received February 22, 1995; accepted August 2, 1995.
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