Pioglitazone induces vascular smooth muscle cell apoptosis through a peroxisome proliferator-activated receptor-gamma, transforming growth factor-beta1, and a Smad2-dependent mechanism.
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)-beta in rat aortic VSMC. Pioglitazone at 100 micromol/l increased apoptosis without affecting DNA synthesis, and this effect was reversed by an anti-TGF-beta1 antibody. Extracellular TGF-beta1 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-beta1 release, and selective phospho-Smad2 nuclear recruitment. Management of Smad signaling on VSMC might provide future clinical benefits in vascular diseases.
Redondo
Santiago
S
Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.
Ruiz
Emilio
E
Santos-Gallego
Carlos G
CG
Padilla
Eugenia
E
Tejerina
Teresa
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D015870:Gene Expression; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D047495:PPAR gamma / Q000502:physiology*; D000077205:Pioglitazone; D051381:Rats; D051899:Smad2 Protein; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D015534:Trans-Activators / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D045162:Thiazolidinediones; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000077205:Pioglitazone