Activation of Peroxisome Proliferator-Activated Receptor &ggr; Suppresses Telomerase Activity in Vascular Smooth Muscle Cells

Activation of the peroxisome proliferator-activated receptor (PPAR) &ggr;, the molecular target for insulin sensitizing thiazolidinediones used in patients with type 2 diabetes, inhibits vascular smooth muscle cell (VSMC) proliferation and prevents atherosclerosis and neointima formation. Emerging evidence indicates that telomerase controls key cellular functions including replicative lifespan, differentiation, and cell proliferation. In the present study, we demonstrate that ligand-induced and constitutive PPAR&ggr; activation inhibits telomerase activity in VSMCs. Telomerase reverse transcriptase (TERT) confers the catalytic activity of telomerase, and PPAR&ggr; ligands inhibit TERT expression through a receptor-dependent suppression of the TERT promoter. 5′-deletion analysis, site-directed mutagenesis, and transactivation studies using overexpression of Ets-1 revealed that suppression of TERT transcription by PPAR&ggr; is mediated through negative cross-talk with Ets-1–dependent transactivation of the TERT promoter. Chromatin immunoprecipitation assays further demonstrated that PPAR&ggr; ligands inhibit Ets-1 binding to the TERT promoter, which is mediated at least in part through an inhibition of Ets-1 expression by PPAR&ggr; ligands. In VSMCs overexpressing TERT, the efficacy of PPAR&ggr; ligands to inhibit cell proliferation is lost, indicating that TERT constitutes an important molecular target for the antiproliferative effects of PPAR&ggr; ligands. Finally, we demonstrate that telomerase activation during the proliferative response after vascular injury is effectively inhibited by PPAR&ggr; ligands. These findings provide a previously unrecognized mechanism for the antiproliferative effects of PPAR&ggr; ligands and support the concept that PPAR&ggr; ligands may constitute a novel therapeutic approach for the treatment of proliferative cardiovascular diseases.

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