(Circulation. 1997;95:1554-1559.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Monoclonal Antibody to P-Selectin and Analogue of Sialyl Lewis X on Cyclic Flow Variations in Stenosed and Endothelium-Injured Canine Coronary Arteries
From the Third Department of Internal Medicine and the Institute of Cardiovascular Diseases, Kurume (Japan) University School of Medicine.
Correspondence to Hisao Ikeda, MD, PhD, The Third Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830 Japan.
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Abstract |
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Background A fundamental role of cell adhesion molecules is implicated in the disease processes of acute coronary syndromes. We have shown an increase in the soluble form of P-selectin in these syndromes, suggesting the important interaction between P-selectin and sialyl Lewis X (SLeX) for the pathophysiology of these syndromes. To further test this, we examined the effects of a monoclonal antibody against P-selectin (PB1.3) and a carbohydrate analogue of SLeX (SLeX-OS) on cyclic flow variations (CFVs) in stenosed and endothelium-injured canine coronary arteries.
Methods and Results Anesthetized, open-chest dogs (n=48) were divided into six groups after CFVs were established. Dogs received intravenous normal saline, PB1.3 (1 mg/kg bolus), a low dose (5 mg/kg bolus) or a high dose (40 mg/kg bolus) of SLeX-OS followed by an infusion (5 mg·kg-1·h-1) for 60 minutes, a combination of PB1.3 and SLeX-OS (low dose), or a combination of a nonblocking antibody against P-selectin (PNB1.6, 1 mg/kg) and SLeX-OS (low dose). Although saline, PB1.3, SLeX-OS (low dose), and the combination of PNB1.6 and SLeX-OS (low dose) did not affect CFVs, the high dose of SLeX-OS and the combination of PB1.3 and SLeX-OS (low dose) significantly reduced CFVs.
Conclusions These findings indicate that the high dose of SLeX-OS and the combination of PB1.3 and the low dose of SLeX-OS provide protection against CFVs. Thus, the adhesive interaction between P-selectin and SLeX may play an important role in mediating CFVs in this model.
Key Words: selectins • platelets • sialyl Lewis X • leukocytes • thrombosis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Platelet aggregation and thrombus formation secondary to plaque disruption at the sites of coronary atheroma play a prominent role in the pathophysiology of acute coronary syndromes, including unstable angina and myocardial infarction.1 2 3 In clinical studies, coronary angiographic4 and angioscopic5 observations have clearly demonstrated the presence of thrombus formation in the early course of these syndromes. Thus, it is likely that acute vascular injury at the site of an atherosclerotic coronary artery activates thrombus formation through a complex cascade of cellular interactions.
Adhesion molecules such as integrins, selectins, and immunoglobulin
superfamilies have been implicated in the disease processes of acute
coronary syndromes6 7 and may play an important role in
the first step of the thrombus formation at the culprit lesion of the
coronary artery. Indeed, blockade of platelet IIb/IIIa integrin by the
monoclonal antibody 7E3 has been shown to inhibit platelet aggregation
in experimental8 and clinical studies,9
indicating the importance of cell-cell adhesive interactions on the
thrombotic process. However, whether the in vivo action of other
adhesion molecules contributes to platelet-mediated thrombosis is
largely unknown. Among adhesion molecules, the glycoprotein P-selectin
is a member of the selectin family and is located in both 
-granules
of platelets10 and Weibel-Palade bodies of endothelial
cells.11 12 After cellular activation by agonists such as
thrombin13 and oxygen free radicals,14
P-selectin is rapidly translocated onto the cell surface and binds a
sialylated carbohydrate structure, SLeX, expressed on
leukocytes through a calcium-dependent lectinlike
mechanism.15 16 Furthermore, analysis of the complementary
DNA demonstrated the possible presence of a soluble form of P-selectin
in blood that possesses a deleted transmembrane segment derived from
alternative splicing of mRNA.17 18 Recently, we showed
that the soluble form of P-selectin markedly increased in acute
coronary syndromes of unstable angina19 and myocardial
infarction.20 These findings may suggest that the
pathophysiology of the acute coronary syndromes is closely related to
coronary arterial thrombi through the cellular interactions among
platelets, leukocytes, and endothelial cells associated with P-selectin
and SLeX. In the present study, to further elucidate the
pathophysiology of acute coronary syndromes, we used an experimental
canine model to test the hypothesis that adhesive interactions of
P-selectin and SLeX are involved in platelet-mediated
thrombus formation in vivo. Three different agents, PB1.3, PNB1.6, and
SLeX-OS, were used to test this hypothesis in dogs with
CFVs in stenosed and endothelium-injured coronary arteries.
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Methods |
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Surgical Preparation
All experiments were conducted in accordance with the guidelines for animal experimentation of the Animal Research Committee of the Kurume University School of Medicine. Healthy mongrel dogs (15 to 20 kg) anesthetized with sodium pentobarbital (30 mg/kg) were ventilated with a ventilator. A thoracotomy was performed in the fifth left intercostal space, and the heart was suspended in a pericardial cradle. Polyethylene catheters were placed in the right atrium for drug infusion. A segment of the left anterior descending coronary artery was gently dissected free from the surrounding tissue, and a pulsed Doppler flow probe (Hartley Instruments) was placed proximal to the constricting cylinder. CBF velocity was measured with a pulsed Doppler flow system (model VF-1, Crystal Biotech). Arterial blood gasses and body temperature were maintained within normal physiological ranges. Aortic pressure was monitored with a micromanometer (Millar Instruments, Inc) placed in the femoral artery. Before the coronary arterial constriction, dogs were allowed to stabilize for 30 minutes, then control hemodynamics, including heart rate, systolic and diastolic aortic blood pressures, and phasic and mean CBF velocities, were recorded on an eight-channel recorder (Recti-Horiz-8K, San-ei). After control measurements were obtained, the endothelium of the exposed left anterior descending coronary artery was injured by gentle squeezing of the artery with cushioned forceps. Then a cylindrical constrictor was placed around the injured coronary artery distal to the flow probe to reduce the phasic CBF velocity to
40% of the control level,
eliminating reactive hyperemia after 15 seconds of temporary coronary
occlusion. Subsequently, CFVs developed in 48 of 56 dogs.
Experimental Protocol
After 60 minutes of stabilization of CFVs, drugs were
administered intravenously according to the following protocols. Dogs
(n=48) were divided into six treatment groups. Group 1 (n=10) received
a bolus of saline followed by a continuous infusion of saline (1 mL/h).
Group 2 (n=7) received a bolus of PB1.3 (1 mg/kg). Group 3 (n=8)
received a bolus of low-dose SLeX-OS (5 mg/kg) followed by
a continuous infusion of 5
mg·kg-1·h-1
for 60 minutes. Group 4 (n=6) received a bolus of high-dose
SLeX-OS (40 mg/kg) followed by a continuous infusion of 5
mg·kg-1·h-1
for 60 minutes. Group 5 (n=11) received a combination of PB1.3 and
low-dose SLeX-OS at the same doses and in the same manners
as used for groups 2 and 3, respectively. Group 6 (n=6) received a
combination of PNB1.6 (1 mg/kg bolus) and low-dose SLeX-OS
at the same dose and in the same manner as used in group 5. To assess
effects of treatments, the severity of CFVs was evaluated by monitoring
mean CBF (mL/min), phasic and mean coronary nadir flow velocities (%
control), and the frequency (cycles/h) for 60 minutes before and after
treatments. For determination of CBF, flow velocity near the center of
the vessel was recorded by use of the pulsed Doppler principle, and
flow velocity was calculated by a digital planimeter. The
cross-sectional area of the vessel was approximated to an inside
diameter of the Doppler flow probe, ranging from 2.0 to 2.5 mm. Then
mean CBF was derived by multiplication of mean flow velocity by the
cross-sectional area.21 The peak and nadir flow velocities
in both phasic and mean CBF were expressed as a percentage of
unconstricted CBF velocity (control). The nadir flow velocity was
calculated by averaging the three lowest flow velocities recorded
before and after treatments, as done by Ashton et al.22 23 24
In dogs that exhibited only two flow restorations after the treatment,
nadir flow velocity was calculated by averaging the two.
Statistical Analysis
Values are presented as mean±SEM. The effects of treatments on
CFVs at different time periods were compared by repeated-measures ANOVA
with a post hoc Scheffé's test. Differences were considered
statistically significant at P<.05.
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Results |
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The hemodynamic data from the six treatment groups of dogs are shown in the Table
and Figures.
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Before Development of CFVs (Stenosis in Table
)
Endothelial injury and coronary constriction decreased the
averaged peak phasic CBF velocity to 38% to 42% of baseline (control)
and mean CBF velocity to 47% to 51% of baseline (control). Heart
rate, aortic pressure, and peak phasic and mean flow velocities were
similar among 6 groups.
After Development of CFVs and Before Treatment (60-Minute CFVs in
Table)
No significant changes were observed in heart rates and in aortic
systolic and diastolic blood pressures after the development of CFVs.
The peak phasic and mean CBF velocities were similarly decreased among
the six groups. The phasic coronary nadir flow velocity was decreased
to 7% of control and mean coronary nadir flow velocity to 10% to 13%
of control (P=NS among the groups). The frequency and the
mean CBF of CFVs was 8.2 to 8.9 cycles/h and 6.5 to 6.8 mL/min,
respectively (Fig 2). These values were also similar among the groups.
Thus, the severity of CFVs was similar among them. These values were
similar to those of other reports.22 23 24
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Effects of Treatments on CFVs (After Treatment in Table)
The effects of saline, PB1.3 alone, low-dose SLeX-OS
alone, high-dose SLeX-OS alone, a combination of PB1.3 and
low-dose SLeX-OS, and a combination of PNB1.6 and low-dose
SLeX-OS are shown in the Table and Figs 1 and 2. There were no significant effects of treatments
on heart rate and aortic pressure in the six groups. Treatment with
saline (group 1), PB1.3 alone (group 2), or low-dose
SLeX-OS alone (group 3) did not cause a significant change
in the coronary nadir flow velocity or the frequency or the mean CBF of
CFVs. In group 4, high-dose SLeX-OS alone significantly
increased the coronary nadir flow velocity (P<.05) and the
mean CBF (P<.05) and significantly decreased the frequency
of CFVs (P<.05). In group 5, a combination of PB1.3 and
low-dose SLeX-OS significantly increased the coronary nadir
flow velocity (P<.05) and the mean CBF (P<.05)
and significantly decreased the frequency of CFVs (P<.05).
During the period between 30 and 60 minutes after treatment in groups 4
and 5, the increases in the coronary nadir flow velocity and mean CBF
and the decreases in the frequency of CFVs were more apparent. In group
6, the combination of PNB1.6 and low-dose SLeX-OS did not
affect the coronary nadir flow velocity or the frequency or the mean
CBF of CFVs.
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Discussion |
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The episodes of CFVs, as originally described by Folts et al,25 are caused by recurrent platelet aggregation and subsequent dislodgment at the coronary stenotic site with endothelial injury. Furthermore, we have previously shown that conscious dogs with CFVs manifest the pathophysiology of acute coronary syndromes in humans, including unstable angina, myocardial infarction, and ischemic sudden death.26 In the clinical setting, CFVs have also been observed during coronary angioplasty in some patients with unstable angina.27 In the present study, the most important findings were that high-dose SLeX-OS or the combination of PB1.3 and low-dose SLeX-OS significantly reduced CFVs. These findings may suggest that the adhesive interaction of P-selectin and SLeX is involved in mediating CFVs in stenosed and endothelium-injured coronary arteries.
In the present study, to examine the role of the adhesion molecules in the thrombotic process, we used a canine model of coronary artery thrombosis that is characterized by CFVs. This model has many characteristics similar to those of acute coronary syndromes in humans, such as ST-segment elevation, depending on the fluctuation of CBF during the episode of CFVs.26 Previous histological studies demonstrated in the animal model with CFVs that numerous platelets and leukocytes were present on the stenotic site adjacent to the thrombi,22 suggesting that cellular interactions between platelets and leukocytes may be involved in the thrombotic process of CFVs. Thus, interactions between P-selectin expressed on platelets and SLeX expressed on leukocytes may play a role in CFVs in this model. To test this possibility, we examined the effects of PB1.3 and SLeX-OS on CFVs.
In this study, PB1.3 was used for investigating the potential role of
P-selectin in the thrombotic process of CFVs. This monoclonal antibody
is of the IgG1 isotype and reacts with P-selectin on the activated
platelet surface in not only humans but also other
mammals.28 29 30 Furthermore, the action of PB1.3 is specific
to P-selectin, because it does not cross-react with other selectin
families, including E- and L-selectins.28 A previous study
showed that the intravenous administration of PB1.3 provides a
dose-dependent protection against leukocyte-mediated lung injury in
rats and that the maximum and plateau protections are observed with a
dose of 1 mg/kg.28 In other studies, it was reported
that doses of 1 to 2 mg/kg of PB1.3 were effective for ameliorating
myocardial reperfusion injury.29 30 31 Therefore, 1 mg/kg of
PB1.3 was chosen in the present study. Sialic acid and fucose are known
to be crucial components of carbohydrate ligands for selectin-mediated
adhesion. Oligosaccharide-containing structures of both sialic acid and
fucose, such as SLeX-OS, could function as ligands to
selectins. It was reported that SLeX-OS competes with
native SLeX expressed on leukocytes, leading to the
inhibition of platelet-leukocyte adhesion.32 The
intravenous administration of SLeX analogues protected
against leukocyte-mediated rat lung injury in a dose-dependent manner
from 0.25 to 2.5 mg/kg.33 In another study using cats,
administration of 10 mg/kg IV resulted in significant cardioprotective
effects against ischemia-reperfusion injury, but 3 mg/kg did
not.34 Lefer et al32 demonstrated significant
cardioprotection against canine ischemia-reperfusion injury with
injection of 5 mg/kg IV. In addition, it has been observed that a
continuous infusion of SLeX-OS (5
mg·kg-1·h-1)
combined with a bolus injection (5 mg/kg) is as effective in
blocking the interaction between SLeX and P-selectin as 1
mg/kg bolus administration of PB1.3 (S. Tojo and coworkers, unpublished
work). Accordingly, we chose a dose of 5 mg/kg as a bolus injection
along with 5
mg·kg-1·h-1
continuous infusion in group 3 (low-dose group). In this study, we did
not use a nonfucosylated analogue of SLeX-OS (sialyl
lactosamine) missing a key fucose residue required for recognition by
P-selectin. Thus, it was not known whether the effect of
SLeX-OS on CFVs was specific. However, previous studies
clearly demonstrated that a nonfucosylated analogue of
SLeX-OS did not protect against ischemia-reperfusion injury
in various experimental animals,32 35 36
P-selectin–mediated rat lung injury,33 traumatic
shock–induced rat tissue injury,37 and thrombin- or
histamine-mediated leukocyte rolling in rat mesenteric
venules.38 39 Thus, it is likely that the
SLeX-OS used in this study provided beneficial effects as a
specific selectin blocker.
Because P-selectin and SLeX could act together on cellular adhesions, we anticipated that the single blockade of P-selectin or SLeX should theoretically reduce CFVs. However, we observed no effect of either PB1.3 or low-dose SLeX-OS alone on CFVs. There are several possibilities to account for this. First, the interaction between P-selectin and SLeX may not play a role in this dog model. Second, the doses of PB1.3 and SLeX-OS may have been too small. Third, it may be necessary to block both P-selectin and SLeX. To examine these possibilities, a higher dose of SLeX-OS (40 mg/kg bolus injection with 5 mg·kg-1·h-1 continuous infusion) was administered, which significantly reduced CFVs. The combination of PB1.3 and low-dose SLeX-OS significantly reduced CFVs. A nonblocking antibody against P-selectin, PNB1.6, combined with low-dose SLeX-OS did not affect CFVs. These results indicate that blocking the interaction between P-selectin on platelets and SLeX on leukocytes and blocking either site were effective in reducing CFVs. These findings suggest that the adhesive interaction between P-selectin on platelets and SLeX on leukocytes plays an important role in mediating CFVs in stenosed and endothelium-injured canine coronary arteries.
Our results suggest the activation of P-selectin and SLeX in the present model. Although we cannot elucidate mechanisms of the activation of these adhesion molecules from this study, several possibilities may be considered. First, it is possible that thrombin may have upregulated the surface expression of P-selectin,13 because the surface expression of P-selectin occurs immediately on exposure to thrombin. Moreover, because it has been shown that thrombin is an important mediator of CFVs,40 thrombin levels appear to be quite high in this model. Second, it is possible that oxygen free radicals may have upregulated the activation of adhesion molecules. We41 42 and others43 have shown that oxygen free radicals, such as superoxide anion and hydrogen peroxide, are other important mediators of CFVs. Recently, oxygen free radicals were shown to induce the prolonged expression of P-selectin on the endothelial cell surface, which results in enhanced leukocyte adherence.14 Thus, it is possible that P-selectin on endothelial cells may be upregulated during the episode of CFVs. However, since the coronary vascular wall at the stenotic site is mechanically injured in the present model and the endothelium may no longer be present, the possibility that P-selectin expressed on endothelial cells plays a role in mediating CFVs may be small.
The present study demonstrated for the first time, to the best of our knowledge, that the inhibition of an adhesive interaction between P-selectin and SLeX could reduce CFVs in stenosed and endothelium-injured canine coronary arteries. Our results may suggest that the adhesive interaction between P-selectin and SLeX contributes importantly to the pathophysiology of acute coronary syndromes in humans. The inhibition of the adhesive interaction between P-selectin and SLeX could become an attractive therapeutic modality of acute coronary syndromes in humans.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We gratefully acknowledge the generous supply of PB1.3, PNB1.6, and SLeX-OS from Shinichiro Tojo, PhD, of the Sumitomo Pharmaceutical Co (Osaka, Japan). The authors are also very grateful to Kimiko Kimura for her technical assistance.
Received August 14, 1996; revision received October 24, 1996; accepted November 4, 1996.
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  S. Yokoyama, H. Ikeda, N. Haramaki, H. Yasukawa, T. Murohara, and T. Imaizumi Platelet P-selectin plays an important role in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates J. Am. Coll. Cardiol., April 19, 2005; 45(8): 1280 - 1286. [Abstract] [Full Text] [PDF]
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 T. Murohara, H. Ikeda, Y. Otsuka, M. Aoki, N. Haramaki, A. Katoh, Y. Takajo, and T. Imaizumi Inhibition of Platelet Adherence to Mononuclear Cells by {alpha}-Tocopherol: Role of P-Selectin Circulation, July 13, 2004; 110(2): 141 - 148. [Abstract] [Full Text] [PDF]
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S. Kanaya, H. Ikeda, N. Haramaki, T. Murohara, and T. Imaizumi Intraplatelet Tetrahydrobiopterin Plays an Important Role in Regulating Canine Coronary Arterial Thrombosis by Modulating Intraplatelet Nitric Oxide and Superoxide Generation Circulation, November 13, 2001; 104(20): 2478 - 2484. [Abstract] [Full Text] [PDF]
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D. Manka, R. G. Collins, K. Ley, A. L. Beaudet, and I. J. Sarembock Absence of P-Selectin, but Not Intercellular Adhesion Molecule-1, Attenuates Neointimal Growth After Arterial Injury in Apolipoprotein E-Deficient Mice Circulation, February 20, 2001; 103(7): 1000 - 1005. [Abstract] [Full Text] [PDF]
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 P. Zoldhelyi, P. J. Beck, R. J. Bjercke, J. C. Ober, X. Hu, J. M. McNatt, S. Akhtar, M. Ahmed, F. J. Clubb Jr., Z.-Q. Chen, et al. Inhibition of coronary thrombosis and local inflammation by a noncarbohydrate selectin inhibitor Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H3065 - H3075. [Abstract] [Full Text] [PDF]
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 M. L. Schermerhorn, M. Tofukuji, P. R. Khoury, L. Phillips, P. R. Hickey, F. W. Sellke, J. E. Mayer Jr, and D. P. Nelson Sialyl LewisX oligosaccharide preserves cardiopulmonary and endothelial function after hypothermic circulatory arrest in lambs J. Thorac. Cardiovasc. Surg., August 1, 2000; 120(2): 230 - 237. [Abstract] [Full Text] [PDF]
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 H. Ikeda, T. Ueyama, T. Murohara, H. Yasukawa, N. Haramaki, H. Eguchi, A. Katoh, Y. Takajo, I. Onitsuka, T. Ueno, et al. Adhesive Interaction Between P-Selectin and Sialyl Lewisx Plays an Important Role in Recurrent Coronary Arterial Thrombosis in Dogs Arterioscler. Thromb. Vasc. Biol., April 1, 1999; 19(4): 1083 - 1090. [Abstract] [Full Text] [PDF]
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 H. Eguchi, H. Ikeda, T. Murohara, H. Yasukawa, N. Haramaki, S. Sakisaka, and T. Imaizumi Endothelial Injuries of Coronary Arteries Distal to Thrombotic Sites : Role of Adhesive Interaction Between Endothelial P-Selectin and Leukocyte Sialyl LewisX Circ. Res., March 19, 1999; 84(5): 525 - 535. [Abstract] [Full Text] [PDF]
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Y. Merhi, P. Provost, P. Chauvet, J.-F. Theoret, M. L. Phillips, and J.-G. Latour Selectin Blockade Reduces Neutrophil Interaction With Platelets at the Site of Deep Arterial Injury by Angioplasty in Pigs Arterioscler. Thromb. Vasc. Biol., February 1, 1999; 19(2): 372 - 377. [Abstract] [Full Text] [PDF]
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