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

Abstract

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)-␤1/Smad-2 pathway was involved. We isolated human internal mammary artery VSMC from patients who had undergone coronary-artery bypass graft. Pioglitazone (100 M) 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-␤1/Smad-2 pathway was involved. Pioglitazone rapidly increased the extracellular TGF-␤1 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.

Evaluation of vitamin B12 effects on DNA damage induced by pioglitazone

“…These concentrations were based on previous studies that used cell cultures systems [17,33] and showed protective effect of vitamin B12 on DNA damage of drugs other than pioglitazone [17]. Based on results of the current study, investigation of a range of concentrations of the combination pioglitazone and vitamin B12 is recommended for future studies.…”

Effects of transforming growth factor-β1 and vascular endothelial growth factor 165 gene transfer on Achilles tendon healing

“…TGF-β1 exerts its neovascularization effects at several levels: control of vascular cell proliferation, maintenance of differentiation, and increased immunomodulatory and anti-inflammatory actions. Some traditional drugs such as aspirin (Redondo et al, 2003;Nakamura et al, 2006) and pioglitazone (Redondo et al, 2005;Ruiz et al, 2007) act on the TGF-β1 pathway. TGF-β1 is also known to enhance tendon repair during the fibrosis period in vitro and vivo by increasing cell proliferation, migration, and the synthesis of both collagen and proteoglycan.…”

Role of TGF-β1 and MAP Kinases in the Antiproliferative Effect of Aspirin in Human Vascular Smooth Muscle Cells

“…In VSMC, its canonical pathway involves signalling by ALK-5 receptor, which phosphorylates the Smad family proteins and translocate into the nucleus to regulate gene expression [8]. The ALK-5/phospho-Smad2 (PSmad2)-dependent signalling pathway has been linked to apoptosis in human VSMC [9]. Nevertheless, in cultured VSMC the importance of TGF-β1-dependent p38 MAPK signalling when TGF-β1 induces proliferation arrest in the absence of apoptosis has equally been described [10].…”