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Cardiovascular Research 2005 65(4):907-912; doi:10.1016/j.cardiores.2004.11.027
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Copyright © 2004, European Society of Cardiology

The effects of PPAR-{gamma} ligand pioglitazone on platelet aggregation and arterial thrombus formation

Dayuan Lia, Kui Chena, Nandita Sinhaa, Xingjiang Zhanga, Yin Wanga, Anjan K. Sinhaa, Francesco Romeod and Jawahar L. Mehtaa,b,c,*

aDepartment of Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, United States
bDepartment of Physiology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, United States
cDepartment of Biophysics, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, United States
dDepartment of Cardiology, University of Rome "Tor Vergata", Rome, Italy

* Corresponding author. University of Arkansas for Medical Sciences, 4301 W. Markham St., Slot 532, Little Rock, AR 72205, United States. Tel.: +1 501 296 1401; fax: +1 501 686 6180. Email address: mehtajl{at}uams.edu

Received 20 August 2004; revised 12 November 2004; accepted 23 November 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Background: It has been suggested that peroxisome proliferator-activated receptor (PPAR)-{gamma} ligands reduce the development of atherosclerosis and myocardial ischemia–reperfusion injury; both of these phenomena are associated with platelet activation. We postulated that PPAR-{gamma} activation would inhibit platelet activation and intra-arterial thrombus formation.

Methods and results: Sprague–Dawley rats were fed chow mixed with pioglitazone (1 or 10 mg/kg/day) for 7 to 10 days. A filter soaked in 30% FeCl3 was applied around the abdominal aorta to study the patterns of arterial thrombogenesis. The aortic blood flow was continuously monitored using an ultrasonic Doppler flow probe. ADP and arachidonic acid-induced platelet aggregation and the expression of constitutive nitric oxide synthase (cNOS) and thrombomodulin in aorta were measured. Pioglitazone feeding delayed the time to occlusive thrombus formation by 40% (P<0.01 vs. control, n=9) without affecting the weight of the thrombus. ADP- as well as arachidonic acid-induced platelet aggregation was also inhibited by pioglitazone feeding (P<0.01 vs. control, n=9). Pioglitazone feeding also upregulated the aortic expression of cNOS and thrombomodulin; both are considered important factors in platelet aggregation and thrombus formation in vivo. The effect of a high dose (10 mg/kg/day) of pioglitazone was not more potent than that of a low dose (1 mg/kg/day).

Conclusion: These results indicate that pioglitazone administration decreases platelet aggregation and delays intra-arterial thrombus formation in rats, at least partially, by an increase in the expression of cNOS and thrombomodulin.

KEYWORDS Arterial thrombosis; cNOS; PPAR-{gamma} agonist; Thrombomodulin


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Diabetes and atherosclerosis are common health problems in the Western world. It is well recognized that diabetes is a critical factor in atherogenesis. Treatment of diabetes significantly reduces progression of atherosclerosis and resultant complications [1]. There is increasing evidence that agonists of peroxisome proliferator-activated receptors (PPARs), such as pioglitazone, are beneficial in managing diabetes [2,3].

PPARs are members of the nuclear receptor super-family that modulate gene expression upon ligand activation [4]. One of the three major subtypes, the PPAR-{gamma} is widely expressed in the cardiovascular system and is involved in the regulation of tissue inflammation [5], production of reactive oxygen species (ROS) [6], smooth muscle cell growth [7], lipoprotein metabolism [8] and coagulation cascade [9]. PPAR-{gamma} ligands, such as pioglitazone, have been shown to exert potent anti-atherogenic effects, both in vitro and in vivo [10,11]. In recent studies, PPAR-{gamma} ligands have been shown to markedly reduce myocardial injury following ischemia–reperfusion [12]. We found that PPAR-{gamma} ligands protect myocardium from ischemia–reperfusion injury, at least in part, via reduction in p67-phos NADPH oxidase, marker of oxidant stress [13].

One of the major causes of acute myocardial ischemia in humans is rupture of the atherosclerotic plaque and formation of a platelet-rich thrombus. Oxidant stress present in atherosclerosis has been shown to facilitate platelet aggregation [14]. We speculated that pioglitazone may modulate platelet aggregation and thereby intra-arterial thrombogenesis. The present study was designed to test this hypothesis.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
Sprague–Dawley rats (male, weight 300–350 g) were used in this study. The rats (n=9) were randomly fed regular rat chow mixed with pioglitazone 1 or 10 mg/kg/day (Takeda, Lincolnshire, IL) for 7 to 10 days. At the end of the feeding period, thrombus formation was examined in all rats. Nine other rats fed regular chow were used to study arterial thrombus formation. Nine other rats were fed regular chow or pioglitazone 10 mg/kg/day for 7 days and subjected to sham surgery. Blood and aortic tissues were harvested for measurements described below. The study was approved by the appropriate Institutional Animal Care Committee and conforms to NIH guidelines.

2.1. Model of arterial thrombosis
The arterial thrombus model has been described previously by us [15,16]. In brief, animals were anesthetized with sodium pentobarbital (30 mg/kg). The abdominal cavity was opened and approximately 1.2 cm of the abdominal aorta was isolated. The aortic blood flow was continuously recorded using an ultrasonic Doppler flow probe (Crystal Biotech, Holliston, MA).

Whatman paper soaked in 29% FeCl3 was wrapped around the external surface of the aorta. After the thrombus was formed, the exposed aorta was removed and the aortic segment with thrombus was weighed. Blood was collected for measuring platelet aggregation. The abdominal aorta proximal to the thrombus was saved for measurement of expression of endothelial constitutive nitric oxide synthase (cNOS) and thrombomodulin.

2.2. Platelet aggregation
Blood was gently mixed with 3.8% sodium citrate (9:1), centrifuged at 1200 rpm for 10 min at room temperature to obtain platelet-rich plasma (PRP), and centrifuged again at 3000 rpm for 15 min to obtain platelet-poor plasma. Platelet count in PRP was counted and kept at about 2–3 x 108 cells/ml. ADP (final concentration 20 µM) and arachidonic acid (final concentration 0.5 µM) were used as stimuli for platelet aggregation. These concentrations of ADP and arachidonic acid have been used for induction of aggregation of rat platelets by us and others [17–19]. All aggregation studies were conducted in a four-channel Chronolog aggregometer in duplicate.

2.3. Semiquantitative RT-PCR for cNOS and thrombomodulin
Total RNA (5 µg) extracted from aortas was reverse-transcripted with Oligo dT (Promega) and M-MLV reverse transcriptase (Promega) at 37 °C for 1 h. Two microliters of the reverse-transcripted material was amplified with Taq DNA polymerase (Promega) using specific primers for rat cNOS and thrombomodulin. Primer sequences of rat cNOS were sense-TAC TTG AGG ATG TGG CTG and antisense-GTC TTC TTC CTG GTG ATG. Primer sequences of rat thrombomodulin were sense-GAC GCT GCA AAA CTT CTG AGG GAT and antisense-TCC TCC GGC TTC AAG TCC TCC CTA. The reaction condition of PCR for both was 94 °C 1 min, 60 °C 45 s, 72 °C 2 min for 33 cycles. The products of PCR amplified samples were visualized on 1.2% agarose gels using ethidium bromide. Each specific mRNA band was normalized with house-keeping gene GADPH.

2.4. Western analysis for cNOS and thrombomodulin
Aortic lysate from each rat (30 µg per lane) was separated by SDS-PAGE, and transferred to nitrocellulose membranes. After incubation in blocking solution (4% non-fat milk, Sigma), membranes were incubated with 1:1000 dilution primary antibody to rat cNOS (BD Translaboratory) and thrombomodulin (Santa Cruz) for overnight at 4 °C. Membranes were washed and then incubated with 1:2000 dilution second antibody (Amersham) for 1 h, and the membranes were detected with the ECL system, and relative intensities of protein bands were analyzed by Scan-gel-it software [16].

2.5. Statistical analysis
All data represent mean of duplicate samples from nine rats in each group. Data are presented as mean ± S.D. Statistical significance in multiple comparisons was determined among independent groups in which ANOVA followed by Fisher's PLSD test indicated the presence of significant differences. A P value <0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. Time to thrombus formation, thrombus weight and platelet aggregation
Application of FeCl3 resulted in formation of a stable clot in the aorta, as indicated by cessation of blood flow. The formation of blood clot and resultant flow pattern in control rats has been published earlier [15,16]. Time to thrombus formation in the control rats was 20.5 (mean) min. Time to arterial thrombus formation in rats fed with pioglitazone was greater when compared to that in rats fed regular diet (30 ± 4 min, P<0.01) (Fig. 1, top panel). There was no spontaneous dissolution of the clot in any of the animals whether fed pioglitazone-rich or regular chow. However, despite delay in thrombus formation, pioglitazone did not affect aortic thrombus weight (Fig. 1, bottom panel).


Figure 1
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  		Fig. 1 The time to thrombus formation, as indicated by cessation of flow, was delayed markedly in rats fed with pioglitazone compared to rats fed with regular diet. High-dose of pioglitazone did not show more potent effect than the low-dose of pioglitazone (top panel). Summary of data on thrombus weight in rats fed with regular chow, or chow mixed with pioglitazone 1 or 10 mg/kg. Administration of pioglitazone to rats did not change thrombus weight (bottom panel). Data (mean ± S.D.) shown are from nine animals in each group.

 
We had speculated that high-dose of pioglitazone would be more potent effects than the low-dose of pioglitazone on parameters of arterial thrombogenesis. However, we found no differences between high-dose and low-dose of pioglitazone in prolonging time to arterial thrombosis or the weight of the thrombus.

Next, we measured platelet aggregation as it is a critical component in arterial thrombus formation. We found that platelet aggregation induced by both ADP and arachidonic acid was markedly attenuated in rats fed pioglitazone compared to rats fed regular diet (P<0.01) (Fig. 2). To examine the direct effects of pioglitazone on platelet aggregation, we isolated platelets from rats fed regular diet, and then incubated the platelets with pioglitazone at 0.1, 1 and 10 µM concentration. However, we found that pioglitazone did not inhibit platelet aggregation in response to ADP or arachidonic acid (data not shown). This indicates that pioglitazone must modulate some components of platelet function during prolonged contact.


Figure 2
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  		Fig. 2 Summary of data on platelet aggregation-induced by ADP and arachidonic acid in rats fed with regular chow, or chow mixed with pioglitazone 1 or 10 mg/kg. Administration of pioglitazone to rats markedly inhibited platelet aggregation. Again, low-dose and high-dose of pioglitazone had similar effects on platelet aggregation-induced by ADP and arachidonic acid. Data (mean ± S.D.) shown are from nine separate animals in each group.

 
3.2. cNOS and thrombomodulin gene expression
It is well known that cNOS and thrombomodulin play important roles in maintaining endothelial integrity and keeping the platelets in inactivated state. In this study, we examined the gene expression of cNOS and thrombomodulin in aortic segments close to the site of thrombus formation. We found that pioglitazone increased the basal expression (both mRNA and protein) of cNOS (P<0.01). Expression of thrombomodulin in aortas of rats fed with pioglitazone was also enhanced by pioglitazone feeding (P<0.01) (Figs. 3 and 4Go). In this experimental model, we found that expression of cNOS mRNA and protein, which was lower in arterial segments subjected to thrombosis in control animals, was increased similarly by both doses of pioglitazone (Fig. 3). Thrombomodulin expression was low during thrombus formation in rats fed control diet, and pioglitazone feeding upregulated its expression in aorta segments despite application of FeCl3 (Fig. 4).


Figure 3
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  		Fig. 3 cNOS expression in aortic homogenates from rats fed different diets. cNOS expression was reduced in rats fed with regular chow and subjected to thrombosis (P<0.01). Feeding of rats with pioglitazone-rich chow increased expression of cNOS. High-dose of pioglitazone did not show more potent effect than the low-dose of pioglitazone. Data (mean ± S.D.) shown are from nine separate experiments.

 

Figure 4
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  		Fig. 4 Expression of thrombomodulin (TM) in aortic homogenates from rats fed different diets. Expression of TM was not reduced in rats fed with regular chow and subjected to thrombosis. However, feeding with chow enriched with pioglitazone significantly increased expression of thrombomodulin (P<0.01). Both doses of pioglitazone were equally effective. Data (mean ± S.D.) shown are from nine rats in each group.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
In the present study, we found that pioglitazone feeding significantly reduced platelet aggregation and delayed arterial thrombus formation in the rat model. There was no difference between high-dose and low-dose of pioglitazone on platelet aggregation or time to arterial thrombus formation. Pioglitazone feeding significantly enhanced the expression of cNOS and thrombomodulin in aortas of rats, which may relate to both inhibition of platelet aggregation and delay in thrombus formation.

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors that regulate lipoprotein metabolism, glucose homeostasis and inflammation [5,8,15]. The PPAR family consists of three proteins (-{alpha}, -{delta} and -{gamma}) [20]. Recent studies [6,21–23] suggest that PPAR-{gamma} activation decreases atherogenesis, not only by correcting metabolic disorders, but also through direct effects on the vascular wall. PPAR-{gamma} agonists modulate the recruitment of leukocytes to endothelial cells [6], control inflammatory response [21] and activation of monocytes/macrophages [22], and regulate inflammatory cytokine production by smooth muscle cells [23]. Experiments using animal models of atherosclerosis and clinical studies in humans strongly support an anti-atherosclerotic role for PPAR-{alpha} and -{gamma} in vivo.

Platelet activation and aggregation and thrombosis in atherosclerotic plaques are critical steps, particularly during acute complications of atherosclerosis. Although many studies [6,21–23] have shown that PPARs modulate inflammatory cytokines, cNOS and endogenous antioxidants, there is a paucity of information on the role of PPARs on arterial thrombogenesis. Ishizuka et al. [24] showed that platelet aggregation in response to ADP, collagen and arachidonic acid is decreased in the presence of 0.1–1 µM troglitazone and 500 µM vitamin E for 60 min. However, pioglitazone did not inhibit ADP-, collagen-, or arachidonic acid-induced platelet aggregation. Pretreatment with troglitazone and vitamin E, but not with pioglitazone, resulted in reductions in thrombin-induced phosphatidic acid production, hydrolysis of phosphatidylinositol 4,5-bisphosphate by phospholipase C, and 47-kDa protein phosphorylation. Arachidonic acid-induced PKC-alpha and -beta activation in membrane fraction was suppressed by pretreatment with troglitazone and vitamin E, but not with pioglitazone. Separately, troglitazone and pioglitazone stimulated PI 3-kinase activity, but arachidonic acid-induced PI 3-kinase activation was suppressed by pretreatment with troglitazone and pioglitazone for 60 min. These results suggest that troglitazone and vitamin E, but not pioglitazone, have a modest inhibitory effect on platelet aggregation via suppression of the arachidonic acid-induced activation of phosphoinositide signaling in human platelets. We also show that incubation of platelets with pioglitazone (1 and 10 µM) for 60 min did not inhibit platelet aggregation induced by APD and arachidonic acid in vitro. However, when rats were fed with pioglitazone for 7 to 10 days, they exhibited a significantly attenuated platelet aggregation in response to ADP and arachidonic acid. Further investigation of arterial thrombus formation showed that pioglitazone delayed time to arterial thrombus formation. These results indicate that prolonged contact pioglitazone in vivo modulates platelet aggregating response ex vivo and this relates to reduction of arterial thrombogenesis.

To further identify how pioglitazone may inhibit platelet aggregation and thrombogenesis, we measured vascular cNOS and thrombomodulin, which are important modulators of vascular tone, platelet aggregation and thrombosis [25,26]. Vascular endothelium possesses several properties to defend against thrombus formation; and in this process, NO is a key modulator. It is a potent vasodilator and platelet inhibitory molecule generated from L-arginine by the enzyme NOS, which is expressed constitutively by the endothelium [27]. It would, therefore, be expected that loss of endothelium during arterial injury would lead to vasospasm and platelet aggregation. In the present study, we found that rats fed with pioglitazone revealed markedly increased expression of cNOS compared to rats fed with regular chow despite application of FeCl3, a potent oxidant stimulus. Upregulation of cNOS may be a basis of attenuated platelet aggregation and, hence, delay in arterial thrombus formation. Studies from other groups [28,29] also show that PPAR-{gamma} ligands, such as rosiglitazone, upregulate cNOS gene expression.

Thrombomodulin–protein C pathway is a major anti-thrombotic mechanism present in endothelial cells, and an important modulator of inflammation. Kanehara et al. [30] investigated the effect of pioglitazone on the expression of thrombomodulin in a human monocyte/macrophage cell line, the human acute monocytic leukemia (THP-1) cells. Pioglitazone dose-dependently upregulated thrombomodulin expression by THP-1 cells accompanied by upregulation of thrombomodulin cofactor activity for thrombin-dependent protein C activation, whereas tissue factor mRNA expression was not. In the present study, we found that rats fed with pioglitazone markedly increased both mRNA and protein of thrombomodulin. Upregulation of thrombomodulin may be another factor in delaying thrombus formation in this study, in concert with inhibition of platelet aggregation.

In summary, this study provides evidence, for the first time, that pioglitazone attenuates arterial thrombus formation, potentially via increasing expression of cNOS and thrombomodulin. These findings may be of clinical significance.


   Notes
 
* Supported by Takeda Pharmaceuticals North America, Lincolnshire, IL and a Scientist Development Grant from the American Heart Association.

Time for primary review 20 days


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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I. W Campbell
Pioglitazone -- an oral antidiabetic agent and metabolic syndrome modulator. Can theory translate into practice?
The British Journal of Diabetes & Vascular Disease, July 1, 2005; 5(4): 209 - 216.
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