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Diabetes 54:811-817, 2005
© 2005 by the American Diabetes Association, Inc.

Pioglitazone Induces Vascular Smooth Muscle Cell Apoptosis Through a Peroxisome Proliferator-Activated Receptor-{gamma}, Transforming Growth Factor-ß1, and a Smad2-Dependent Mechanism

Santiago Redondo, Emilio Ruiz, Carlos G. Santos-Gallego, Eugenia Padilla, and Teresa Tejerina

From the Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain

Thiazolidinediones, such as pioglitazone, seem to exert direct antiatherosclerotic and antirestenotic effects on type 2 diabetes, in part due to an induction of vascular smooth muscle cell (VSMC) apoptosis. We aimed to study the role of transforming growth factor (TGF)-ß in rat aortic VSMC. Pioglitazone at 100 µmol/l increased apoptosis without affecting DNA synthesis, and this effect was reversed by an anti-TGF-ß1 antibody. Extracellular TGF-ß1 levels were rapidly increased after treatment with pioglitazone in a peroxisome proliferator-activated receptor (PPAR)-{gamma}-dependent mechanism because this secretion was blocked by the PPAR-{gamma} inhibitor GW9662. Pioglitazone subsequently increased the nuclear recruitment of phospho-Smad2, without any effect on protein expression. According to our results, we propose that the apoptotic effect of pioglitazone on VSMC depends on the following sequence: PPAR-{gamma} activation, TGF-ß1 release, and selective phospho-Smad2 nuclear recruitment. Management of Smad signaling on VSMC might provide future clinical benefits in vascular diseases.

Address correspondence and reprint requests to Teresa Tejerina, Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. E-mail: teje{at}med.ucm.es


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Home page
 J. Pharmacol. Exp. Ther.Home page
E. Ruiz, S. Redondo, A. Gordillo-Moscoso, and T. Tejerina
Pioglitazone Induces Apoptosis in Human Vascular Smooth Muscle Cells from Diabetic Patients Involving the Transforming Growth Factor-beta/Activin Receptor-Like Kinase-4/5/7/Smad2 Signaling Pathway
J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 431 - 438.
[Abstract] [Full Text] [PDF]


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Copyright © 2005 by the American Diabetes Association.