Pioglitazone Induces Vascular Smooth Muscle Cell Apoptosis Through a Peroxisome Proliferator-Activated Receptor-γ, Transforming Growth Factor-β1, and a Smad2-Dependent Mechanism

Abstract

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)-β in rat aortic VSMC. Pioglitazone at 100 μmol/l increased apoptosis without affecting DNA synthesis, and this effect was reversed by an anti-TGF-β1 antibody. Extracellular TGF-β1 levels were rapidly increased after treatment with pioglitazone in a peroxisome proliferator-activated receptor (PPAR)-γ-dependent mechanism because this secretion was blocked by the PPAR-γ 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-γ activation, TGF-β1 release, and selective phospho-Smad2 nuclear recruitment. Management of Smad signaling on VSMC might provide future clinical benefits in vascular diseases.