Copyright © 2004, European Society of Cardiology
The effects of PPAR-
ligand pioglitazone on platelet aggregation and arterial thrombus formation
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
Background: It has been suggested that peroxisome proliferator-activated receptor (PPAR)-
ligands reduce the development of atherosclerosis and myocardial ischemia–reperfusion injury; both of these phenomena are associated with platelet activation. We postulated that PPAR- 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- agonist; Thrombomodulin
* Supported by Takeda Pharmaceuticals North America, Lincolnshire, IL and a Scientist Development Grant from the American Heart Association.
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