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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 31, 2007; DOI: 10.1124/jpet.106.114934

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Received for publication October 6, 2006.
Revised January 26, 2007.
Accepted for publication January 29, 2007.

Pioglitazone induces apoptosis in human vascular smooth muscle cells from diabetic patients involving the TGF-beta/ALK-4/5/7/Smad2 signaling pathway

Emilio Ruiz 1, Santiago Redondo 1, Antonio Gordillo 1, Teresa Tejerina 1*

1 Universidad Complutense, School of Medicine

* Address correspondence to: E-mail: teje{at}med.ucm.es

Abstract

Aims. Alterations in vascular wall remodeling are a typical complication in type 2 Diabetes Mellitus due to an imbalance between cell proliferation and apoptosis. In this context, we have previously shown that vascular smooth muscle cells (VSMC) from diabetic patients were resistant to induced apoptosis. Thiazolidinediones, such as pioglitazone, seem to exert direct antiatherosclerotic effects on type 2 diabetes. We aimed to study whether pioglitazone was able to induce apoptosis in VSMC from diabetic patients (DP) and, if so, whether the TGF-{beta}1/Smad-2 pathway was involved. Methods. Human internal mammary artery VSMC were isolated from patients who had undergone coronary-artery bypass graft. Results. Pioglitazone (100 µM) induced apoptosis in human VSMC from diabetic and non-diabetic patients (NDP), analyzed by DNA fragmentation and by degradation of Bcl-2, in high-glucose-containing medium (15 and 25 mM). This apoptotic effect was inhibited by the ALK-4/5/7/Smad2 inhibitor SB-431542, denoting that the TGF-{beta}1/Smad-2 pathway was involved. Pioglitazone rapidly increased the extracellular TGF-{beta}1 levels and concomitantly induced phosphorylation of Smad2 in VSMC from DP and NDP. Conclusion. We demonstrated that pioglitazone induced apoptosis in human VSMC from DP, which are strongly resistant to the induced apoptosis. This effect of pioglitazone might contribute in the treatment of alterations of vascular remodeling in type 2 Diabetes Mellitus.


Key words: apoptosis, diabetes, peroxisome proliferator activated receptor, pioglitazone, transforming growth factor beta, vascular smooth muscle cells


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