© 2000 American Heart Association, Inc.
Vascular Biology |
Adenovirus-Mediated Human Tissue Kallikrein Gene Delivery Inhibits Neointima Formation Induced by Interruption of Blood Flow in Mice
From the Gene Therapy Section of the National Laboratory of the National Institute of Biostructures and Biosystems (C.E., M.B.S., A. Munaò, P.M.), Osilo, Italy; Laboratorio di Patologia Vascolare (C.E., S.S., A. Minasi, M.C.C.), Istituto Dermopatico dell’ Immacolata (IDI-IRCCS), Roma, Italy; Institute of Internal Medicine (P.M.), School of Medicine, University of Sassari, Sassari, Italy; and the Department of Biochemistry and Molecular Biology (J.C., L.C., J.A., K.-F.L.), Medical University of South Carolina, Charleston.
Correspondence to Costanza Emanueli, PhD, Gene Therapy Section, National Laboratory of the National Institute of Biostructures and Biosystems, via Brigata Sassari, 13, 07033 Osilo, Sassari, Italy. E-mail emanueli{at}yahoo.com
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Abstract—Tissue kallikrein cleaves kininogen to produce vasoactive kinin peptides. Binding of kinins to bradykinin B2 receptors on vascular endothelial cells stimulates the release of nitric oxide and prostacyclin, thus activating the cGMP and cAMP pathways. In this study, we evaluated the effects of adenovirus-mediated human tissue kallikrein gene (Ad.CMV-cHK) delivery in a mouse model of arterial remodeling induced by permanent alteration in shear stress conditions. Mice underwent ligature of the left common carotid artery and were injected intravenously with saline or 1.8x109 plaque-forming units of Ad.CMV-cHK or control virus (Ad.CMV-LacZ). Fourteen days after surgery, morphometric analysis revealed that Ad.CMV-cHK reduced neointima formation by 52% (P<0.05) compared with Ad.CMV-LacZ. Expression of human tissue kallikrein (HK) mRNA was detected in mouse carotid artery, aorta, kidney, heart, and liver, and recombinant HK was present in the urine and plasma of mice receiving HK gene. Kallikrein gene transfer resulted in increases in urinary kinin, cGMP, and cAMP levels. The protective action of Ad.CMV-cHK on neointima formation was significantly reduced (P<0.05) in mice with knockout of the kinin B2 receptor gene compared with wild-type control mice (J129Sv mice). In contrast, the effect of Ad.CMV-cHK was amplified (P<0.05) in transgenic mice overexpressing human B2 receptor compared with wild-type control mice (c57/Bl6 mice). Thus, the inhibitory effect of recombinant kallikrein on structural alterations caused by the interruption of blood flow appears to be mediated by the B2 receptor. These results provide new insight into the role of the tissue kallikrein-kinin system in vascular remodeling and suggest the application of HK gene therapy to treat restenosis and atherosclerosis.
Key Words: human tissue kallikrein • gene delivery • neointima formation • bradykinin B2 receptors • mice, transgenic and knockout
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Introduction |
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Restenosis is one of the major complications of percutaneous transluminal angioplasty and can be regarded as a combination of neointima (NI) formation and arterial remodeling triggered by vascular injury. Vascular remodeling also occurs as an adaptive phenomenon in response to chronic hemodynamic alterations aimed at maintaining a predetermined level of shear stress by permanent modifications in vascular geometry.1 2 3 The endothelium is considered a critical mediator of the flow-dependent remodeling process.2 In fact, vascular endothelial cells (VECs), acting as sensors of intraluminal mechanical forces, release growth factors and vasoactive substances able to induce cell proliferation, migration, and death as well as matrix deposition.2
The presence of a local kallikrein-kinin system in the vasculature is firmly established,4–6 and evidence is now emerging regarding the possible participation of this system in vascular remodeling. Tissue kallikrein is a serine protease that cleaves low molecular weight kininogen to produce kinin peptides. Kinins stimulate the release of nitric oxide (NO) and prostacyclin (PGI2) through the activation of bradykinin (BK) B2 receptors expressed by VECs. NO and PGI2 exert antiproliferative and antimigratory effects on vascular smooth muscle cells (VSMCs) by increasing intracellular cGMP and cAMP, respectively.7 8 9 10 11
The contribution of kinins in the protective effect of angiotensin-converting enzyme (ACE) inhibitors against arterial thickening caused by balloon injury was demonstrated in rats by the use of a B2 receptor antagonist.12 13 14 15 Recently, adenovirus-mediated human tissue kallikrein (HK) gene delivery proved to be an efficient strategy to increase local or circulating kinin levels for a limited period of time. By this mechanism, HK gene therapy reportedly prevents the development of hypertension, cardiac hypertrophy, and renal failure16 17 18 and suppresses NI formation in balloon-injured rat arteries.19 Whether the beneficial effect of HK gene therapy can be extended to other models of vascular remodeling remains unknown. Recently, Kumar, Lindner, and colleagues 20 21 have shown that NI formation can be induced in the mouse carotid artery by disrupting local blood flow, a maneuver that causes permanent changes in shear stress conditions. One important feature of this approach is that vascular endothelium is not removed, thus underlining the importance of substances that are specifically released by or targeted to VECs. In addition, availability of a murine model of vascular remodeling is essential to exploit the informative potential of genome manipulation, which is usually carried out in mice.
The aim of the present study was to explore the potential beneficial effects of HK gene delivery on NI formation caused by ligature of the common carotid artery. The effectiveness of gene therapy was tested in wild-type mice as well as in genetically manipulated mice lacking the B2 receptor gene (B2-/- mice)22 23 or carrying an exogenous transgene encoding for the human B2 receptor (HB2 transgenic mice).24
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Methods |
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Preparation of Replication-Deficient Adenovirus Vector Carrying the HK Gene
An adenovirus vector containing the HK gene (Ad.CMV-cHK) was generated as previously described.18 The expression of HK cDNA is under the control of the cytomegalovirus (CMV) enhancer/promoter, followed by a bovine growth hormone poly(A) signal sequence. An adenovirus harboring the ß-galactosidase gene under the control of the CMV enhancer/promoter (Ad.CMV-LacZ) was also prepared as described.26
Animals
All procedures complied with the standards for care and use of
animal subjects as stated in the Guide for the Care and Use of
Laboratory Animals (Institute of Laboratory Animal Resources,
National Academy of Sciences, Bethesda, Md). Experiments were carried
out in male mice (aged 2 to 3 months). Swiss mice were purchased from
Charles River (Varese, Italy).
B2-/- mice, kindly provided by
Dr Fred Hess (Merck Laboratories, Rahway, NJ), were generated by gene
targeting and homologous recombination on a J129Sv genetic
background.22 Wild-type J129Sv mice (Jackson
Laboratory, Bar Harbor, Maine) served as controls for
B2-/- mice.
HB2 transgenic mice were developed on a c57/Bl6
background.24 Wild-type c57/Bl6 mice (Charles River,
Varese, Italy) served as controls for HB2
transgenic mice.
Surgical Procedures and Animal Treatment
In Swiss mice anesthetized with 2,2,2-tribromoethanol
(88 mmol/100 g body wt IP), the left common carotid artery was
exposed and ligated with 6-0 silk just proximal the carotid bifurcation
to disrupt blood flow. At the same occasion, the animals were injected
via the left femoral vein with sterile saline (vehicle) or
1.8x109 plaque-forming units (pfu) of Ad.CMV-cHK
or Ad.CMV-LacZ. In sham-operated mice, the carotid artery was exposed
but not ligated.
Additional Swiss mice, undergoing the same experimental protocol described above, were given 1 of the following compounds for 14 days: the B2 antagonist D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]BK (icatibant, 1 µmol/kg body wt per day IP, by osmotic minipumps), the B1 antagonist des-Arg9-[Leu8]BK (DALBK, 50 nmol/kg body wt per day IP, by osmotic minipumps), or the inhibitor of NO synthase NG-nitro-L-arginine methyl ester (L-NAME, 1.4 mmol/kg body wt per day in drinking water).
In a separate set of experiments, B2-/-, HB2, and their respective wild-type control mice underwent carotid artery ligation and were injected via the left femoral vein with sterile saline (vehicle) or 1.8x109 pfu Ad.CMV-cHK or Ad.CMV-LacZ.
Fourteen days after surgery, mice were euthanized for morphometric analysis. Each group consisted of at least 7 mice.
Hemodynamic Measurements
Systolic blood pressure and heart rate of
unanesthetized Swiss mice were measured by tail-cuff
plethysmography (Visitech) under basal conditions and 3, 7, and 14 days
after carotid ligation and injection of Ad.CMV-cHK (n=6) or Ad.CMV-LacZ
(n=5).
Expression of HK
Evidence of successful infection by systemic Ad.CMV-cHK delivery
was obtained by measuring HK mRNA levels in tissues and recombinant
protein in plasma. Swiss mice (n=3) were injected with Ad.CMV-cHK or
Ad.CMV-LacZ (1.8x109 pfu IV). Three days later,
blood was withdrawn from the hearts of anesthetized mice.
Carotid artery, thoracic aorta, kidney, heart, and liver were isolated
and removed for total RNA extraction by the Trizol method (BRL).
Reverse transcription–polymerase chain reaction (RT-PCR) Southern blot
analysis with the use of specific
oligonucleotide probes for HK (5' primer, 5'-AAC ACA
GCC CAG TTT GT-3'; 3' primer, 5'-CTT CAC ATA AGA CAG CA-3'; and
internal probe, 5'-GACCTCAAAATCCTGCC-3') was performed as previously
described.17 Expression of mouse ß-actin mRNA in tissues
was used as an internal control. Circulating HK levels were determined
by ELISA with use of an antibody that recognizes only the active moiety
of HK.16
Measurements of HK, Kinin, cGMP, and cAMP Levels in Urine
Twenty-four–hour urine collections were obtained under basal
conditions and 3, 7, and 14 days after intravenous
injection of Ad.CMV-cHK or Ad.CMV-LacZ (n=6 mice for each treatment)
from Swiss mice placed in metabolic cages. Urinary HK
levels were determined by ELISA.16 Urinary levels of cGMP
and cAMP were determined by an enzyme immunoassay (Biotrak). Urine
samples for kinin measurements were collected in ethanol to prevent
enzymatic degradation. Kinins were measured by radioimmunoassay
(Phenix), after extraction with Sep-Pak C18 columns (Waters).
Morphometric Analysis
Fourteen days after carotid ligation or sham operation, the mice
were anesthetized and perfusion-fixed at a constant pressure
(100 mm Hg) via the left ventricle with 4%
paraformaldehyde in 0.1 mol/L phosphate buffer (pH
7.3). The whole left common carotid artery was excised and placed for
24 hours in 4% paraformaldehyde. Vessels were then
processed for paraffin embedding. Five serial sections (200 µm
apart) of 3-µm thickness were cut, starting from 1 mm below the
carotid bifurcation and proceeding to the aortic arch. Sections were
stained with hematoxylin-eosin. Morphometric analysis was
performed in a blind fashion by use of a dedicated software package
(KS300, Zeiss). The areas enclosed by the external elastic lamina (EEL)
and internal elastic lamina (IEL) and the length of the IEL and EEL
were measured. IEL was taken as an index of inward remodeling; EEL, as
a measure of vascular constriction. The area of the media was
calculated by subtracting the area delimited by the IEL from the area
delimited by the EEL. The total number of cells in the NI and media was
evaluated at a magnification of x1000 with use of a calibrated grid.
Cellular density in the NI and media was calculated by dividing total
cell count by the respective area. For each carotid artery, the values
obtained from the 5 sections were averaged.
Statistical Analysis
Data are expressed as mean±SEM. Multivariate
repeated measures ANOVA was performed to test for interaction between
time and the grouping factor. In multiple comparisons among independent
groups in which ANOVA and the F test indicated significant differences,
the statistical value was determined according to the method of
Bonferroni. Differences within and between groups were determined by
paired or unpaired Student t test, respectively. A value of
P<0.05 was considered statistically significant.
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Expression of HK After Gene Delivery
The expression of HK mRNA in mice after kallikrein gene delivery was detected by RT-PCR, followed by Southern blot analysis with the use of 3 oligonucleotides specific for HK. Figure 1
shows that HK mRNA can be detected in
the aorta, carotid artery, heart, liver, and kidney but that the RT-PCR
products from mice receiving Ad.CMV-LacZ did not hybridize to the
HK gene probe (top panel). Similar levels of ß-actin mRNA were
detected in tissues of the experimental and control groups, verifying
the quality of RNA in these samples (bottom panel). Three days after
intravenous injection of Ad.CMV-cHK, circulating levels of
immunoreactive HK averaged 145±20 ng/mL. In addition, as shown in
Figure 2A, immunoreactive HK was detected
in the urine, peaking at 7 days after injection. In contrast,
immunoreactive HK levels in plasma and urine were undetectable in mice
injected with Ad.CMV-LacZ (see Figure 2).
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, n=6) in the femoral vein of Swiss mice.
*P<0.05 vs Ad.CMV-LacZ; +P<0.05 vs
basal conditions.
Urinary Kinin, cGMP, and cAMP Levels After Gene Delivery
Urinary kinin, cAMP, and cGMP levels were not altered by
Ad.CMV-LacZ (Figure 2B
through 2D). In contrast, mice treated
with Ad.CMV-cHK showed a 3.8-fold increase in immunoreactive kinin
levels at 7 days after injection (Figure 2B). Urinary cAMP and
cGMP increased by 5.3- and 2.5-fold, respectively (Figure 2C and 2D).
Morphometric Analysis
Consistent with previous studies performed in FVB
mice,20 we found that also in Swiss mice disruption of
carotid blood flow causes a reduction in vessel lumen area that is due
to a combination of NI formation (NI area 41 817±5381
µm2), medial hyperplasia (37 445±5552 versus
23 820±5368 µm2 in sham-operated mice,
P<0.05), and reduction in IEL and EEL lengths (1095±143
versus 1318±137 µm and 1162±92 versus 1404±137 µm,
respectively; P<0.05 for both comparisons). NI was
maximally represented close to the ligation site and
decreased in thickness in the direction of the aortic arch.
In Ad.CMV-LacZ–injected mice, the vascular remodeling response to
carotid ligation was comparable qualitatively and quantitatively to
that observed in mice given saline. In contrast, as shown in Figure 3, Ad.CMV-cHK delivery attenuated NI
formation (21 059±3417 versus 43 885± 2778
µm2 in Ad.CMV-LacZ–treated mice,
P<0.05) without affecting the medial area. As a
consequence, the NI/media ratio was reduced by 52% (0.59±0.18 versus
1.28±0.06 in Ad.CMV-LacZ–treated mice, P<0.01). The
lengths of the IEL and EEL were unaffected by Ad.CMV-cHK delivery
(972±59 and 1064±72 µm versus 1071±133 and 1158±111
µm in Ad.CMV-LacZ–treated mice, respectively; P=NS for
both comparisons).
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Chronic administration of the B1 or the
B2 receptor antagonists did not
change the vascular remodeling response to carotid ligation in
Ad.CMV-LacZ–treated mice (data not shown). However, when these agents
were tested in Ad.CMV-cHK–treated mice, we found that the
B2 antagonist icatibant completely
abrogated the protective effect of HK gene delivery against NI
formation, whereas the B1 receptor
antagonist DALBK was ineffective (Figure 3).
As shown in Figure 4, HK gene transfer
decreased NI total cell count (101±20 versus 268±65 cells in the
cross section Ad.CMV-LacZ group, P<0.01) and increased NI
cell density (22±2 versus 6±1 cells/mm2 in the
Ad.CMV-LacZ group, P<0.001). In contrast, HK gene delivery
produced borderline changes in medial total cell count (149±14 versus
109±10 cells cross section in the Ad.CMV-LacZ group,
P=0.06) and in medial cell density (7±1 versus 5±1
cells/mm2 in the Ad.CMV-LacZ group,
P=0.09). Icatibant contrasted the effect of kallikrein on NI
cell count and density (Figure 4A) without affecting these
parameters in the media (Figure 4B). The
B1 antagonist DALBK did not alter the
effects of HK gene delivery on cellular count and density.
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Figure 5 shows the typical pattern of
vascular remodeling caused by ligature of the carotid artery in Swiss
mice treated with Ad.CMV-LacZ (panel B), Ad.CMV-cHK (panel C), or
Ad.CMV-cHK plus icatibant (panel D).
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In Ad.CMV-LacZ–treated Swiss mice, L-NAME did not alter the remodeling response to carotid ligation. Evaluation of the effect of NO synthase inhibition after HK gene transfer was precluded by a dramatic reduction in the survival rate in the group given L-NAME in combination with Ad.CMV-cHK. In fact, all 12 mice that entered this treatment showed a progressive deterioration of general conditions and died within 7 days.
Effect of Ad.CMV-cHK Delivery on Vascular Remodeling in
B2-/- and HB2 Transgenic
Mice
Morphometric analysis of carotid arteries did not detect
any difference between B2-/-
and HB2 transgenic mice and their respective
wild-type controls, J129Sv and c57/B16, in the absence of vascular
injury as well as after artery ligation (data not shown). However,
genetically manipulated animals differed from controls regarding the
effectiveness of HK in preventing NI formation. In fact, as shown in
Figure 6A (left bars), the protective
effect of Ad.CMV-cHK delivery was reduced in the
B2-/- strain compared with the
wild-type J129Sv strain, leading to a greater NI/media area ratio in
knockout mice (Figure 6C, left bars). Conversely, inhibition of
NI formation by Ad.CMV-cHK was potentiated in HB2
transgenic mice compared with their wild-type controls, c57/Bl6 (Figure 6, right bars).
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Hemodynamic Measurements
As shown in the Table, no change in
systolic blood pressure was observed in Swiss mice after
ligation of the common carotid artery and injection of Ad.CMV-cHK or
Ad.CMV-LacZ. A tendency of the heart rate to increase was observed in
both groups, but this change did not reach statistical significance
(P=0.08).
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Discussion |
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To the best of our knowledge, this is the first study demonstrating a protective role of adenovirus-mediated HK gene delivery against vascular remodeling in the mouse. Another novel discovery is that insertion or deletion of the BK B2 receptor gene respectively enhances or precludes the protective action of the tissue kallikrein gene on NI formation, thus demonstrating the essential role of B2 receptor signaling in this gene therapy approach.
Injury to the arterial wall induces the synthesis of gene products that stimulate smooth muscle cell migration and proliferation, thus leading to intimal hyperplasia. It has been hypothesized that the suppression of tissue kallikrein gene expression in the damaged vessel may contribute to the pathogenesis of restenosis after angioplasty.19 This idea is supported by the observation that kinins, generated from kininogen by tissue kallikrein, inhibit vascular cell proliferation.19 On the basis of this assumption, HK gene delivery has been successfully used to suppress NI formation in the rat balloon-injured carotid artery, an effect that appears to be mediated by activation of the kinin B2 receptor.
A large body of evidence now indicates that a chronic decrease in shear stress can also produce vascular wall alterations similar to those caused by mechanical injury in normal and in atherosclerotic vessels.27 28 29 Therefore, we thought it would be worthwhile to evaluate the efficacy of HK gene delivery in preventing the vascular remodeling caused by permanent alteration in shear stress conditions. To this aim, we exploited the mouse model recently established by Kumar and Lindner,20 in which disruption of blood flow triggers NI formation together with reduction in vessel diameter. In this setting, the proliferative response of VSMCs is thought to be stimulated by the increase in arterial wall tension that occurs proximal to the ligation.27 28
Under basal conditions, we found no difference between B2-/- and wild-type control mice regarding the vascular structure of the carotid artery; neither B2 receptor gene knockout altered vascular remodeling after ligature. Thus, the congenital absence of the B2 receptor neither results in structural vascular abnormalities nor affects the remodeling response to vascular injury. Similarly, NI formation was not worsened by B2 receptor antagonism in Swiss mice injected with Ad.CMV-LacZ. However, a functional B2 receptor appears to be essential for the vascular protection exerted by HK gene delivery. In fact, the suppression of NI formation by Ad.CMV-cHK was abrogated by the B2 receptor antagonist icatibant. These data are in line with the results obtained by Farhy et al15 in the rat balloon-injury model by the use of an ACE inhibitor. In fact, icatibant, which by itself did not worsen NI formation, partially prevented the protective effect of ACE inhibition. Altogether, these results indicate that kinins are indeed able to contrast vascular remodeling, provided that their levels are augmented through pharmacological or genetic interventions.
This assumption, together with the identification of the receptor implicated in the action of Ad.CMV-cHK, was further challenged by the use of murine models in which the endogenous B2 receptor gene was either deleted or added to the human B2 receptor gene. This approach has obvious advantages over the classic use of receptor antagonists, including the possibility of recognizing a correlation between biological effects of HK and the number of copies of the B2 receptor gene. A gene dosage effect was found. In fact, we have shown that the protective action of Ad.CMV-cHK is virtually absent in B2-/- and enhanced in HB2 transgenic mice, thus demonstrating the essential role of the B2 receptor in the beneficial effect of HK gene delivery.
The HK gene was expressed in the vasculature, liver, kidney, and heart after intravenous injection of Ad.CMV-cHK into mice. The secreted nature of the gene product is indicated by the presence of active HK in the circulation and urine. Therefore, suppression of NI formation by Ad.CMV-cHK may be attributable to the effect of recombinant protein either locally expressed or circulating in the blood stream. The protection exerted by Ad.CMV-cHK delivery appears to be limited to a reduction in NI formation, whereas medial hyperplasia or vessel shrinking remained unaffected. The finding that after Ad.CMV-HK treatment total cell count was decreased in the NI and unchanged in the media suggests that HK could act by inhibiting VSMC proliferation. An antiproliferative role of Ad.CMV-HK on cultured VSMCs has been previously shown by Murakami et al.19 In vitro experiments also indicate that the binding of kinins to aortic VSMC receptors stimulates PGI2 formation, with increased cAMP levels and subsequent inhibition of VSMC proliferation.30 The mechanism by which Ad.CMV-HK transfer inhibits vascular growth in vivo may also involve the induction and/or activation of NO synthase. The binding of kinins to vascular endothelial B2 receptor increases NO release from VECs.31 Once released by VECs, NO reaches VSMCs, where it activates guanylate cyclase, thus increasing the production of cGMP, a potent inhibitor of VSMC proliferation and migration.7 8 32 Accordingly, previous studies showed that kinin-stimulated NO release contributes to the beneficial effect of ACE inhibitors in balloon injury–induced remodeling by reducing VSMC migration from the tunica media to the NI.15 33 As stated above, cell count in the media was unchanged by Ad.CMV-cHK treatment. We would expect that if HK blocked VSMC migration to NI without affecting the proliferation rate, the total number of cells would be increased in the tunica media. Because this was not the case, it is likely that VSMC migration and proliferation were inhibited by Ad.CMV-cHK treatment. Further studies that use markers of cellular turnover may help dissect the importance of these 2 mechanisms. The finding that NI cell density was augmented in the Ad.CMV-HK group favors a suppressive role of HK against matrix accumulation.
Although activation of cAMP and cGMP pathways by HK is well documented in the present study, investigation of the role of NO was precluded by the fact that L-NAME dramatically reduced the survival rate in mice given the HK gene, possibly because of severe bronchoconstriction and hypertension.34 35 L-NAME by itself did not affect remodeling in animals treated with Ad.CMV-LacZ. This is in apparent discordance with studies of vascular remodeling in endothelial NO synthase knockout mice, which show increased wall thickness after carotid ligation, compared with wild-type control mice.9 However, it should be noted that only the external carotid artery was ligated in endothelial NO synthase knockout mice,9 whereas in our experimental setting, blood flow was completely interrupted by ligature of the common carotid artery. Abrogation of blood flow may have reduced the basal release of NO from vascular endothelium to such an extent that no further decrease would be expected with NO synthase inhibition.
Although carotid occlusion could disturb blood flow to the brain and baroreceptor function, this had no consequence on systemic blood pressure. Failure to detect changes in blood pressure could be due to the fact that adaptive adjustments may have already occurred at the time the first measurements were performed. In addition, because of an efficient collateral flow, ligature of 1 carotid artery may be not sufficient to induce brain ischemia in mice. Disturbance in baroreceptor function is supported by the tachycardia observed after surgery.
In conclusion, we have demonstrated the feasibility and efficacy of adenovirus-mediated HK gene transfer in a mouse model of vascular remodeling. These results underline the importance of the kallikrein-kinin system in vascular biology and open a new avenue for gene therapy in vascular diseases.
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Acknowledgments |
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We gratefully acknowledge Telethon-Olnus for financial support (grant A.105) and National Institutes of Health grants HL-29397 and HL-52196. In addition, we would like to thank Dr Renzo Filippetti, Vittorio Lelii, and Leandro Travaglini from the Università Cattolica del Sacro Cuore (Rome, Italy) for their assistance in the animal care.
Received August 16, 1999; accepted February 25, 2000.
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