doi: 10.1161/01.ATV.0000231512.15115.25
© 2006 American Heart Association, Inc.
Letters to the Editor |
Pioglitazone Reduces Endothelial Microparticles in the Metabolic Syndrome
From the Division of Metabolic Diseases, Center of Excellence for Cardiovascular Research, University of Naples SUN, Italy.
Correspondence to Dario Giugliano, MD, PhD, Division of Metabolic Diseases, University of Naples SUN, Piazza Miraglia 2, Naples, 80021 Italy. E-mail dario.giugliano{at}unina2.it
Emerging evidence indicates that in patients without diabetes but with features of the metabolic syndrome, the peroxisome proliferator-activated receptor-
(PPAR-) ligand pioglitazone exerts direct effects on inflammation and endothelial dysfunction which may be independent of amelioration of insulin resistance.1,2 In particular, in nondiabetic patients with low high density lipoprotein cholesterol (HDL-C) and the metabolic syndrome, a 12-week treatment with pioglitazone significantly raised HDL-C and favorably affected lipoprotein particle size, markers of inflammation, and adipokines without changes in triglycerides, low density lipoprotein cholesterol, or weight.1 Improvements in endothelial function and circulating markers of inflammation were also observed in nondiabetic subjects with hypercholesterolemia or hypertension receiving a 8-week treatment with pioglitazone.2 In this perspective, PPAR- ligands may find room among possible pharmacological treatments for the metabolic syndrome, as rosiglitazone can decrease the prevalence of the syndrome by 
30%.3,4
In recent years, the interest for endothelial cell–derived submicroscopic membranous vesicles, termed microparticles, has substantially increased, not only because of their procoagulant properties, but also because of their putative role in inflammatory processes and their ability to directly affect endothelial functions.5,6 To our knowledge, there are no reported studies that investigated the effect of PPAR- ligands on circulating microparticles.
We evaluated the short-term effects of pioglitazone on circulating endothelial microparticles in subjects with the metabolic syndrome as defined by NCEP (ATPIII)7; subjects were excluded if they had diabetes mellitus, cardiovascular disease, or if they took any medication, including vitamin or mineral supplements. The 10 subjects volunteered after informed consent to participate in this randomized, double-blind, crossover, pilot study of pioglitazone (45 mg/d) or placebo for 4 weeks. Endothelial microparticles (EMP) were measured by flow cytometry. In brief, 50 µL of platelet-poor plasma was incubated (20 minutes) with either 4 µL of anti-CD31-fluorescein isothiocyanate (FITC) (Pharmingen), plus 4 µL anti-CD42b-PE (Becton Dickinson), then diluted with 1 mL of PBS and analyzed on BD FACSCalibur cytometer. Endothelial microparticles were defined as CD31+/CD42– particles. The rationale of 2-color method (CD31 and CD42b) was that significant CD31 occurs on both EMP and platelet microparticles, whereas CD42b is restricted to platelets, allowing discrimination between them. The possibility of leukocyte microparticles (CD31+/CD45+) was tested but accounted for negligible percentage of all CD31+ microparticles in both normal and obese women. Control isotope immunoglobulin IgG1 and IgG2a antibodies were obtained from Becton Dickinson. Events were counted by triggering on the fluorescence signal of phycoerythrin, above background noise, on the y axis of the dot plot, whereas the green signal of CD31-FITC was on the x axis (4-decade log scales, x and y). Values are reported as counts per microliter.
The results are given in the Table. Compared with placebo, treatment with pioglitazone caused a significant decrease of circulating EMP. There was no relation between the change in insulin sensitivity (HOMA, fasting plasma glucose in mmol/L x fasting serum insulin in µU/mL/25) and the decrease of circulating EMP (r=–0.04, P=0.75). Pioglitazone produced a significant increase in HDL-C without changing body weight. The results of this preliminary study show that in nondiabetic subjects with the metabolic syndrome a short-term pioglitazone treatment may reduce circulating EMP independent of amelioration of insulin sensitivity. This novel finding adds to the increasing list of antiinflammatory and antiatherogenetic effects of PPAR- ligands,8 and may contribute to the improvement of the cardiovascular outlook in subjects with the metabolic syndrome.
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Acknowledgments
Disclosures
None.
References
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2. Campia U, Matuskey LA, Panza JA. Perixosome proliferator-activated- activation with pioglitazone improves endothelium-dependent dilation in nondiabetic patients with major cardiovascular risk factors. Circulation. 2006; 113: 867–875.
3. Esposito K, Ciotola M, Carleo C, Schisano B, Saccomanno F, Sasso FC, Cozzolino D, Assaloni R, Merante D, Ceriello A, Giugliano D Effect of rosiglitazone on endothelial function and inflammatory markers in patients with the metabolic syndrome. Diabetes Care. 2006; 29: 1071–1076.
4. Giugliano D, Esposito K. Optimal treatments for the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2006; 26: e30.
5. VanWijk MJ, VanBavel E, Sturk A, Nieuwland R. Microparticles in cardiovascular diseases. Cardiovasc Res. 2003; 59: 277–287.
6. Diamant M, Tushuizen ME, Sturk A, Nieuwland R. Cellular microparticles: new players in the field of vascular disease. Eur J Clin Invest. 2004; 34: 392–401.[CrossRef][Medline] [Order article via Infotrieve]
7. Executive Summary of the Third Report of the national Cholesterol Education Program (NCEP) expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATP III). J Am Med Assoc. 2001; 285: 2486–2497.
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