Biphasic effect of pioglitazone on isolated human endothelial progenitor cells: Involvement of peroxisome proliferator-activated receptor-γ and transforming growth factor-β1

Santiago Redondo; Mihail Hristov; Denis Gümbel; Teresa Tejerina; Christian Weber

doi:10.1160/TH06-10-0593

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 97(06): 988-997
DOI: 10.1160/TH06-10-0593

Endothelium and Vascular Development

Schattauer GmbH

Biphasic effect of pioglitazone on isolated human endothelial progenitor cells: Involvement of peroxisome proliferator-activated receptor-γ and transforming growth factor-β1

Santiago Redondo

¹Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain

²Institute for Molecular Cardiovascular Research (IMCAR)

,

Mihail Hristov

²Institute for Molecular Cardiovascular Research (IMCAR)

³Interdisciplinary Center for Clinical Research “BIOMAT”, RWTH University Hospital, Aachen, Germany

,

Denis Gümbel

²Institute for Molecular Cardiovascular Research (IMCAR)

,

Teresa Tejerina

¹Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain

,

Christian Weber

²Institute for Molecular Cardiovascular Research (IMCAR)

³Interdisciplinary Center for Clinical Research “BIOMAT”, RWTH University Hospital, Aachen, Germany

› Author Affiliations

Abstract

Summary

Endothelial progenitor cells (EPCs) have been implicated in vascular repair and found to be functionally impaired in patients with diabetes. We evaluated the effects of the anti-diabetic drug pioglitazone on human EPC function and the involvement of PPAR-γ and TGF-β1. EPCs in culture were characterized at day 7 by the development of colony-forming units (CFUs) and flow cytometry assessment of differentiation marker (DiI-ac-LDL/lectin, KDR and CD31). Adhesion on fibronectin and fibrinogen in flow was analyzed as functional parameter. Treatment with pioglitazone for 72 hours increased the number of EPC-CFUs, DiI-ac-LDL⁺/lectin⁺, CD31⁺ and KDR⁺ EPCs at 1 μM but not at 10 μM. Since pioglitazone did not significantly alter proliferation and apoptosis in cultured EPCs, the increase in EPC number was most likely attributable to augmented adhesion and differentiation. Indeed, pioglitazone increased EPC adhesion in flow at 1 μM, an effect prevented by PPAR-γ and β2-integrin blockade. In contrast, pioglitazone did not promote EPC adhesion at 10 μM; however, increased adhesion became evident by co-incubation with a blocking TGF-β1 antibody. As determined by ELISA, pioglitazone induced a persistent increase in TGF-β1 secretion only at 10 μM when a significantly elevated expression of endoglin, the accessory receptor forTGF-β1, was also observed. Taken together, pioglitazone exerts biphasic effects on the function of isolated EPCs, causing a PPAR-γ-dependent stimulation at 1 μM and a TGF-β1-mediated suppression at 10 μM. These results may help to define optimal therapeutic doses of pioglitazone for improving endothelial dysfunction.

Keywords

Endothelial - pioglitazone - pharmacology - growth factors - adhesion

Full Text

References

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