Pioglitazone induces apoptosis in human vascular smooth muscle cells from diabetic patients involving the transforming growth factor-β/activin receptor-like kinase-4/5/7/Smad2 signaling pathway
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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. Here, we aimed to study whether pioglitazone was able to induce apoptosis in VSMC from diabetic patients (DP) and, if so, whether the transforming growth factor (TGF)-β1/Smad-2 pathway was involved. We isolated human internal mammary artery VSMC from patients who had undergone coronary-artery bypass graft. Pioglitazone (100 μM) induced apoptosis in human VSMC from diabetic and nondiabetic 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 activin receptor-like kinase-4/5/7/Smad2 inhibitor 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin- 2-yl-1H-imidazol-2-yl)benzamide (SB-431542), denoting that the TGF-β1/Smad-2 pathway was involved. Pioglitazone rapidly increased the extracellular TGF-β1 levels and concomitantly induced phosphorylation of Smad2 in VSMC from DP and NDP. Thus, 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. Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics.
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4 [4 (1,3 benzodioxol 5 yl) 5 (2 pyridinyl) 1h imidazol 2 yl]benzamide; DNA fragment; pioglitazone; Smad2 protein; transforming growth factor beta; transforming growth factor beta receptor 1; apoptosis; article; cell proliferation; controlled study; coronary artery bypass graft; diabetic patient; DNA determination; drug effect; human; human tissue; minimum inhibitory concentration; priority journal; protein degradation; protein phosphorylation; smooth muscle fiber; vascularization; Activin Receptors; Activin Receptors, Type I; Aged; Apoptosis; Atherosclerosis; Cells, Cultured; Diabetic Angiopathies; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; PPAR gamma; Protein-Tyrosine Kinases; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad2 Protein; Thiazolidinediones; Transforming Growth Factor beta1
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