(Circulation. 1998;98:2891-2898.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
Platelet-Derived 12-Hydroxyeicosatetraenoic Acid Plays an Important Role in Mediating Canine Coronary Thrombosis by Regulating Platelet Glycoprotein IIb/IIIa Activation
Presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 10–13, 1997, and published in abstract form (Circulation. 1997;96[suppl I]:I-722).
From the Department of Internal Medicine III, Kurume University School of Medicine (A.K., H. Ikeda, T.M., N.H., T.I.), and the Third Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co (H. Ito), Japan.
Correspondence to Hisao Ikeda, MD, Department of Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830, Japan. E-mail ikeikeda{at}med.kurume-u.ac.jp
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Abstract |
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Background—In the thrombotic process of acute coronary syndromes, the pathophysiological role of thromboxane A2 via cyclooxygenase is well established; however, the role of 12-HETE via 12-lipoxygenase is little known. Therefore, we used OPC-29030, a novel specific inhibitor of 12-HETE synthesis, to test whether platelet-derived 12-HETE is involved in mediating cyclic flow variations (CFVs) and platelet aggregation in stenosed and endothelium-injured canine coronary arteries.
Methods and Results—After developing CFVs, dogs received a vehicle or OPC-29030 intravenously. Plasma and intraplatelet 12-HETE levels increased after CFVs. OPC-29030 but not vehicle reduced CFVs, which was associated with decreases in plasma and intraplatelet 12-HETE levels. Cessation of OPC-29030 restored CFVs in association with increases in plasma and intraplatelet 12-HETE levels. ADP and U46619 induced ex vivo platelet 12-HETE production and aggregation. After OPC-29030 administration, the ADP- and U46619-induced increases in ex vivo platelet 12-HETE production and aggregation were inhibited significantly. Platelet aggregation was linearly correlated with platelet 12-HETE production. OPC-29030 suppressed activation of human platelet glycoprotein IIb/IIIa.
Conclusions—OPC-29030 reduced intraplatelet 12-HETE levels, resulting in the inhibition of coronary thrombosis in vivo in dogs. OPC-29030 inhibited human platelet glycoprotein IIb/IIIa activation in vitro. Thus, platelet-derived 12-HETE may play an important role in mediating thrombotic process.
Key Words: platelets • hydroxyeicosatetraenoic acid • platelet aggregation • glycoproteins • thrombosis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Plaque disruption with subsequent thrombus formation has been implicated as a major pathogenic mechanism for the acute coronary syndromes, including unstable angina and acute myocardial infarction.1 2 3 In clinical studies, coronary angioscopic observations have shown the presence of platelet thrombi in these syndromes.4 Experimental studies have also demonstrated that platelet-mediated coronary thrombosis produces pathophysiological manifestations similar to these syndromes.5 Thus, acute vascular injury at the site of coronary atherosclerotic plaque substantially facilitates thrombus formation through a complex cascade of cellular interactions between platelets and vascular endothelial cells.
Metabolites of arachidonic acid play an important role in mediating thrombus formation and in regulating vascular tone.6 Arachidonic acid, which increases dramatically via action of the phospholipase A2-mediated phospholipid hydrolysis,7 is metabolized through 2 major catalytic pathways mediated by 2 different enzymes in platelets.8 One is cyclooxygenase, which produces thromboxane A2 (TXA2), and the other is 12-lipoxygenase, which produces 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which is rapidly converted to 12-hydroxyeicosatetraenoic acid (12-HETE). In experimental3 9 10 and clinical1 11 studies, the pathophysiological role of TXA2 in platelets is well established in thrombus formation at the culprit lesion of the coronary artery. However, it is still unknown whether 12-HETE plays an active role in mediating thrombus formation in vivo, although 12-HETE has been shown to potentiate platelet aggregation in vitro.12
Accordingly, to further investigate the pathophysiology of the acute
coronary syndromes, we tested our hypothesis that
platelet-derived 12-HETE is involved in mediating thrombus
formation in vivo by use of a well-established experimental canine
model.13 14 15
(S)-(+)-6-[3-(1-o-tolylimidazol-2-yl)sulfinylpropoxy]-3,4-dihydro-2(1H)-quinolinone
(OPC-29030) is a newly developed specific inhibitor of
12-HETE synthesis in platelets (Figure 1
), and its efficacy has been established
in vivo.16 Therefore, OPC-29030 was used to test
our hypothesis in dogs. We also examined whether OPC-29030 affects
plasma and intraplatelet levels of 12-HETE and
thromboxane B2
(TXB2) in vivo, inhibits ex vivo platelet
aggregation and 12-HETE production induced by ADP and U46619,
and inhibits human platelet glycoprotein (GP) IIb/IIIa
activation in vitro.
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Methods |
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Surgical Preparation and Experimental Protocol
All experimental protocols were conducted in accordance with the guidelines for animal experimentation issued from the Human and Animal Research Committee of Kurume University School of Medicine. Our canine model of cyclic flow variations (CFVs) was prepared as described previously.5 13 14 15 CFVs developed in 40 of 51 dogs. The remaining 11 dogs were excluded from this protocol.
Dogs (n=40) were divided into 4 groups. After 40 minutes of stabilization of CFVs, drugs were administered intravenously. Group 1 (n=12) received a continuous infusion of the vehicle as control (dimethylformamide; Wako Co) at 100 µg · kg-1 · min-1 for 40 minutes. Groups 2 (n=4), 3 (n=18), and 4 (n=6) received a continuous infusion of OPC-29030 (3, 10, and 20 µg · kg-1 · min-1, respectively) (Otsuka Co) for 40 minutes. All dogs were monitored for an additional 40 minutes after cessation of the treatment. To assess the effects of each treatment, the severity of CFVs was evaluated by their frequency over a period of 40 minutes (cycles/40 min) before, during, and after cessation of the treatment. The severity of CFVs was also evaluated by their coronary blood flow (CBF) velocity (% control) as previously described.15 17
Measurements of Plasma and Intraplatelet 12-HETE and
TXB2 Levels In Vivo
In groups 1 (n=10) and 3 (n=12), to examine plasma 12-HETE and
TXB2 levels before and after the treatments,
blood was sampled from the right atrium and collected into a prechilled
(4°C) siliconized glass tube containing EDTA (7.7 mmol/L at pH
7.4; Sigma Chemical Co), baicalein (a 12-lipoxygenase
inhibitor; 5 µmol/L; Sigma), and
indomethacin (a cyclooxygenase
inhibitor; 50 µmol/L; Sigma). After
centrifugation, supernatants were frozen in liquid
nitrogen and stored at -80°C until assay.
In group 3, to examine the effects of OPC-29030 on intraplatelet 12-HETE (n=12) and TXB2 (n=8) levels, blood was sampled as described above. Collected blood was mixed with EDTA, baicalein, and indomethacin and was kept at 4°C. The platelet pellet was obtained by serial centrifugations, and the pellet was resuspended in modified HEPES–Tyrode's buffer without Ca2+ or Mg2+ and containing EDTA, baicalein, and indomethacin. The platelets were washed twice with the same buffer, and the number of platelet was adjusted to 100 000/mm.3 Eicosanoid extraction was performed by the method described by Raghunath et al.18 Measurements of 12-HETE and TXB2 levels were performed in duplicate with a commercially available competitive enzyme immunoassay kit (Titer Zyme, PerSeptive Diagnostics).
Ex Vivo Platelet Aggregation and 12-HETE Production
In group 1 (n=9) and group 3 (n=10), to assess the effects of
OPC-29030 and of the vehicle on platelet function, ex vivo
platelet aggregation was studied before and after the treatments.
Platelet aggregation study was performed as previously
described.14 Selected agonists and their final
concentrations were ADP 5 to 40 µmol/L (Sigma) and U46619, a
thromboxane mimetic, 50 to 400 ng/mL (Cayman Co). Because
canine platelets do not aggregate in response to U46619 alone,
epinephrine (Sigma) was added at 10 µmol/L before the
addition of U46619.19
In 10 dogs of group 3, the effects of OPC-29030 on platelet 12-HETE production were studied. After platelet aggregation study, ADP- and U46619-stimulated platelet-rich plasmas (PRPs) were centrifuged. Supernatants were then frozen and stored at -80°C until assay. The concentration of 12-HETE was determined as described above. Platelet 12-HETE production was expressed as the difference between the eicosanoid concentrations of agonist-stimulated PRP and those of nonstimulated PRP.
Measurements of Plasma OPC-29030 Levels
In group 3 (n=12), plasma OPC-29030 levels were measured during
and after the OPC-29030 treatment. The measurements were performed with
high-performance liquid chromatography as
previously described.16
Measurements of Intraplatelet cAMP Levels
In group 3 (n=10), to examine the effects of OPC-29030 on
intraplatelet cAMP levels, blood was collected into a prechilled
siliconized glass tube containing EDTA and
isobutylmethylxanthine 0.5 mmol/L (Sigma)
and was kept at 4°C. The platelet pellet was obtained as
described above. The residual pellet was resuspended in modified
HEPES–Tyrode's buffer without Ca2+ or
Mg2+ and containing EDTA and
isobutylmethylxanthine. The platelets were
washed twice with the same buffer, and the number of platelets was
adjusted to 100 000/mm3. Measurements of
intraplatelet cAMP levels were performed in duplicate with a
commercially available competitive enzyme immunoassay kit (Biotrak,
Amersham Pharmacia Biotec).
Analysis of Human Platelet GP IIb/IIIa
Activation
With peripheral blood collected from 5 healthy
volunteers, washed platelets were prepared according to the
previously described method20 and incubated at
22°C for 10 minutes with 300 ng/mL OPC-29030, 1 µmol/L
baicalein, or buffer. Then, the samples were incubated with a
saturating concentration of the FITC-conjugated monoclonal antibody
PAC-1 (Becton-Dickinson), followed by incubation at 22°C for 10
minutes with ADP at 0.05 to 5 µmol/L, U46619 at 0.05 to 5
µmol/L, thrombin at 5 to 500 mU/mL, or buffer. The PAC-1 antibody has
a specificity for an epitope that is exposed on the fibrinogen receptor
GP IIb/IIIa only after an activation-dependent conformational
change.21 The samples were then fixed in
paraformaldehyde 1% at 22°C for 30 minutes and were
analyzed within 2 hours by flow cytometry (Becton-Dickinson).
Background binding, obtained from parallel samples run with
FITC-conjugated immunoglobulin M (Pharmingen) was subtracted from each
test sample. PAC-1 binding in the presence of maximal thrombin (500
mU/mL) and buffer alone was assigned to be 100 U
fluorescence.
Statistical Analysis
Values are presented as mean±SEM. Statistical
comparisons between groups were performed with a paired Student's
t test. Multiple comparisons were analyzed by
repeated-measures ANOVA. The relationship between 2
parameters was analyzed by use of a linear
regression analysis. Differences were considered statistically
significant at a value of P<0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hemodynamics
Before Development of CFVs
Endothelial injury and coronary constriction significantly decreased the averaged peak phasic CBF velocity to 35% to 38% of baseline and the mean CBF velocity to 47% to 52% of baseline. These figures are similar to those reported by Ashton et al.17 Heart rate, aortic pressure, and peak phasic and mean CBF velocities were comparable among the 4 groups (Table
).
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Initial CFVs
No significant changes were observed in heart rate or in
systolic and diastolic aortic pressures after
development of CFVs. The peak phasic and mean CBF velocities were
decreased similarly among the groups. The phasic CBF velocity was
decreased to 12% to 14% of baseline and mean nadir CBF velocity to
11% to 14% of baseline. The averaged frequency of CFVs was 4.1 to 4.3
cycles/40 min. These values were also similar among the 4 groups. Thus,
the severity of CFVs before the treatment was similar among the 4
groups. These figures were similar to those reported by Ashton et
al17 and us5 13 14 15 (Table
).
During Treatment
The treatments did not cause significant changes in heart rate or
aortic pressure in groups 1, 2, and 3, but they did in group 4. In
groups 1 and 2, the treatment did not cause significant changes in the
nadir CBF velocity or the frequency of CFVs. In group 3, OPC-29030
significantly increased the nadir CBF velocity and significantly
decreased the frequency of CFVs in association with increases in plasma
OPC-29030 levels (212±30 ng/mL at 20 minutes and 286±48 ng/mL at 40
minutes) (Figure 2, Table).
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After Cessation of Treatment
In groups 1, 2, and 3, cessation of treatment did not cause
significant changes in heart rate or aortic pressure. In group 4,
cessation of treatment decreased heart rate and increased aortic
pressure, although statistically insignificantly. In groups 1 and 2,
cessation of treatment did not cause significant changes in either
nadir CBF velocity or frequency of CFVs. In group 3, cessation of
OPC-29030 treatment returned the nadir CBF velocity and the frequency
of CFVs to the levels before treatment. Plasma OPC-29030 levels after
cessation of treatment decreased to 68±16 and 31±8 ng/mL at 20 and 40
minutes, respectively (Figure 2). In group 4, cessation of the
OPC-29030 treatment significantly restored CFVs (Table).
Plasma and Intraplatelet 12-HETE and TXB2
Levels
In group 1 (Figure 3A), plasma
12-HETE levels after CFVs were significantly increased compared with
those before CFVs. Neither treatment nor cessation of treatment caused
significant changes in plasma 12-HETE levels. In group 3 (Figure 3B),
plasma 12-HETE levels after CFVs were significantly increased compared
with those before CFVs. OPC-29030 significantly decreased plasma
12-HETE levels. After cessation of treatment, plasma 12-HETE levels
were restored to those observed during initial CFVs. In group 3,
intraplatelet 12-HETE levels changed to the same degree as plasma
levels (Figure 4).
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In group 3, plasma and intraplatelet TXB2 levels were not changed by OPC-29030 treatment (plasma TXB2, 0.91±0.14 ng/mL during CFVs versus 0.99±0.21 ng/mL during treatment, P=NS; intraplatelet TXB2, 0.22±0.05 ng/mL during CFVs versus 0.24±0.05 ng/mL during treatment, P=NS).
Effects of Treatments on Ex Vivo Platelet Aggregation and
12-HETE Production
In group 1, both ADP and U46619 caused comparable
concentration-dependent platelet aggregation before and after
treatment (Figure 5A). In group 3, both
agonist-induced platelet aggregation (Figure 5B) and platelet
12-HETE production (Figure 6)
were significantly suppressed by OPC-29030 compared with those before
treatment. There were significant linear relationships between
platelet aggregation and 12-HETE production after
stimulation with both agonists (Figure 7).
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) and
treatment with vehicle (
). B, Ex vivo platelet aggregation
during initial CFVs (
) and OPC-29030 treatment (
). ADP and U46619
induced platelet aggregation in a concentration-dependent manner.
OPC-29030 significantly reduced platelet aggregation, whereas
vehicle caused no significant changes.
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Intraplatelet cAMP Levels
The intraplatelet cAMP levels did not change at any given time
point (Figure 8).
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Effects of OPC-29030 and Baicalein on Human Platelet GP
IIb/IIIa Activation
As shown in Figure 9, ADP, U46619,
and thrombin caused dose-dependent platelet GP IIb/IIIa activation.
OPC-29030 and baicalein significantly inhibited the platelet GP
IIb/IIIa activation induced by all these agonists.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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As originally described by Folts et al,9 focal platelet aggregation and subsequent dislodgment at the coronary stenotic site result in brief and repeated episodes of coronary occlusion that are characterized by CFVs.10 22 The present model is now established as an in vivo model of coronary arterial thrombosis.23 We previously reported that conscious dogs with CFVs manifest a pathophysiology similar to that of the acute coronary syndromes in humans.5 The major findings of the present study were that (1) there were increases in both plasma and intraplatelet 12-HETE levels after development of CFVs; (2) OPC-29030 reduced CFVs in association with decreases in both plasma and intraplatelet 12-HETE levels, whereas the cessation of OPC-29030 restored CFVs in association with increases in both plasma and intraplatelet 12-HETE levels; (3) OPC-29030 inhibited ex vivo platelet aggregation and 12-HETE production induced by ADP and U46619; and (4) OPC-29030 inhibited agonist-induced activation of human platelet GP IIb/IIIa in vitro. Thus, our results suggest that platelet-derived 12-HETE is critically involved in mediating platelet aggregation and CFVs in vivo in stenosed and endothelium-injured coronary arteries.
In the present study, OPC-29030 at 3 µg · kg-1 · min-1 did not affect CFVs, but OPC-29030 at 20 µg · kg-1 · min-1 significantly reduced CFVs, although this dosage caused systemic hemodynamic changes. Thus, decreases in CFVs by OPC-29030 at 20 µg · kg-1 · min-1 might not be attributable solely to its effects on platelets. In contrast, OPC-29030 at 10 µg · kg-1 · min-1 significantly reduced CFVs without systemic hemodynamic changes. Therefore, the dosage of 10 µg · kg-1 · min-1 was used for the subsequent protocols. The cessation of OPC-29030 treatment significantly restored CFVs. Our data therefore indicate that OPC-29030 reduces CFVs by its antiplatelet effects. To further investigate the role of 12-HETE in the pathogenesis of the thrombotic process of CFVs, we measured plasma and intraplatelet 12-HETE levels. In this connection, a previous in vitro study showed that 12-HETE was produced by aggregated platelets,8 and a previous study using the same dog model with CFVs demonstrated that the 12-HETE synthesis was increased by 10-fold in the stenosed and endothelium-injured coronary arteries.24 In this study, both plasma and intraplatelet 12-HETE levels during CFVs increased significantly compared with those before CFVs. The inhibitory effects of OPC-29030 on CFVs were associated with decreases in both plasma and intraplatelet 12-HETE levels. The IC50 of OPC-29030 for ex vivo platelet 12-HETE inhibition was 0.73 µmol/L (315 ng/mL).16 In this study, when CFVs were inhibited, the plasma concentration of OPC-29030 after treatment was begun was 212±30 and 286±48 ng/mL at 20 and 40 minutes, respectively. Thus, the effective plasma OPC-29030 levels in vivo were close to the value of IC50 in the ex vivo experiment. The cessation of OPC-29030 treatment decreased the plasma OPC-29030 levels to <70 ng/mL and restored CFVs in association with significant increases in plasma and intraplatelet 12-HETE levels. Taken together, our data clearly suggest that platelet-derived 12-HETE plays an important role in the thrombotic process of CFVs in this model.
We used an in vivo model of coronary arterial
thrombosis in this study. Although OPC-29030 treatments significantly
reduced CFVs in association with decreases in intraplatelet 12-HETE
levels, it is not known whether OPC-29030 treatment inhibits
platelet aggregation in association with inhibition of platelet
12-HETE production. To address this issue, we investigated the
effects of OPC-29030 on ex vivo platelet aggregation and 12-HETE
production. ADP and U46619, a thromboxane mimetic,
were chosen as platelet agonists in this study because ADP and
TXA2 are important mediators of
CFVs.9 10 19 In the present study, ADP and
U46619 induced platelet aggregation (Figure 5) and 12-HETE
production (Figure 6) in a concentration-dependent manner. Both
ex vivo platelet aggregation (Figure 5B) and 12-HETE
production (Figure 6) were significantly suppressed after
OPC-29030 treatments, whereas the vehicle did not have this effect
(Figure 5A). Importantly, there was a close linear relationship between
platelet aggregation and intraplatelet 12-HETE
production for ADP and U46619 (Figure 8). These findings
further support the previous studies demonstrating that
12-lipoxygenase inhibitors such as
baicalein25 inhibit in vitro human platelet
aggregation induced by the same agonists as used in this study. Thus,
our data suggest that OPC-29030 inhibits platelet aggregation
through the inhibition of platelet 12-HETE production via
the lipoxygenase pathway. Moreover, our data provide
evidence that, in the cascade of arachidonic acid
metabolism in activated platelets, the
lipoxygenase pathway plays an important role in
mediating platelet aggregation in addition to the
cyclooxygenase pathway, which is implicated in
platelet aggregation in the Folts dog
model.9 10
OPC-29030 is a novel specific inhibitor of 12-HETE synthesis in activated platelets and can be administered in vivo. Indeed, this agent does not inhibit purified cyclooxygenase activity and does not affect platelet TXA2 production stimulated with thrombin (H. Ito, MS, and coworkers, unpublished work). In the present study, OPC-29030 did not have any effects on the plasma and intraplatelet TXB2 levels in vivo. Thus, OPC-29030 does suppress the 12-HETE synthesis in platelets without a significant effect on the cyclooxygenase pathway.16 OPC-29030 is a derivative of cilostazol,16 which is known to inhibit platelet aggregation by elevating intraplatelet cAMP levels.26 In this study, OPC-29030 at 10 µg · kg-1 · min-1 did not affect intraplatelet cAMP levels. Therefore, the beneficial effects of OPC-29030 on CFVs are unlikely to be mediated via the increases in intraplatelet cAMP levels but are more likely to be mediated via the specific inhibition of 12-HETE synthesis in platelets. In this study, OPC-29030 did not increase plasma and intraplatelet TXB2. The exact mechanisms are unclear. However, previous studies have demonstrated that the inhibition of platelet 12-HETE production prevents the increase in intraplatelet [Ca2+],25 which would have nonspecifically inhibited the activation of phospholipase A2 in platelets, leading to no significant changes in plasma and intraplatelet TXB2 levels in this study. Furthermore, it is possible that 12-HPETE, the precursor of 12-HETE, was a platelet-active lipoxygenase metabolite. However, it has been shown that 12-HPETE inhibits platelet activation27 and 12-HETE potentiates platelet activation.12 Hence, this possibility is unlikely.
There are several possible mechanisms by which 12-HETE causes
platelet aggregation. First, 12-HETE may potentiate platelet GP
IIb/IIIa activation, which is the final common pathway of platelet
aggregation28 and a key factor for
coronary thrombosis.29 Once a
platelet is activated, GP IIb/IIIa takes on a new
3-dimensional conformational state and reveals binding sites for
fibrinogen.21 In this work, we studied the
effects of inhibition of platelet 12-HETE synthesis on activation
of human platelet GP IIb/IIIa because there is no available
antibody that reacts with canine platelets. Consequently, OPC-29030
as well as baicalein significantly inhibited human platelet GP
IIb/IIIa activation induced by ADP, U46619, and thrombin (Figure 9).
The concentration of OPC-29030 used in this in vitro study was
comparable to that achieved in a canine model of coronary
arterial thrombosis in vivo. Thus, the present findings
suggest that platelet 12-HETE causes platelet aggregation via
GP IIb/IIIa activation. Second, 12-HETE may upregulate platelet
P-selectin,30 which potentiates the thrombotic
process.31 Recently, we15
and others32 have shown that P-selectin plays an
important role in mediating CFVs in the present model.
Because P-selectin is an important adhesion molecule for the
interaction of platelets and endothelial cells with
leukocytes33 and because it has been demonstrated
that OPC-29030 significantly decreases platelet adhesion onto the
denuded surface of rat aorta under in vivo dynamic flow conditions (T.
Igawa, PhD, and coworkers, unpublished work), the antithrombotic
effect of OPC-29030 in this study may be due to the inhibition of
platelet adhesiveness through the downregulation of P-selectin.
In conclusion, the present study first demonstrates that OPC-29030, a novel specific inhibitor of 12-HETE synthesis, inhibits platelet aggregation and abolishes CFVs in vivo in association with decreases in both plasma and intraplatelet concentrations of 12-HETE. Furthermore, OPC-29030 inhibited human platelet GP IIb/IIIa activation. Our results strongly suggest that platelet-derived 12-HETE contributes to the pathophysiology of thrombus formation in acute coronary syndromes. Thus, the inhibition of 12-HETE via the lipoxygenase pathway in activated platelets could become an attractive therapeutic modality of these syndromes in humans.
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Acknowledgments |
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We gratefully thank Drs Yasushi Ozeki and Fumiko Unemi of the Otsuka Pharmaceutical Co (Tokushima, Japan) for generously supplying OPC-29030. The authors are also very grateful to Kimiko Kimura and Aya Shimizu for their excellent technical assistance.
Received May 5, 1998; revision received August 12, 1998; accepted August 20, 1998.
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