Activation of Peroxisome Proliferator-Activated Receptor γ Suppresses Telomerase Activity in Vascular Smooth Muscle Cells

Abstract

Abstract-Activation of the peroxisome proliferator-activated receptor (PPAR) ␥, 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␥ activation inhibits telomerase activity in VSMCs.Telomerase reverse transcriptase (TERT) confers the catalytic activity of telomerase, and PPAR␥ ligands inhibit TERT expression through a receptor-dependent suppression of the TERT promoter. 5Ј-deletion analysis, site-directed mutagenesis, and transactivation studies using overexpression of Ets-1 revealed that suppression of TERT transcription by PPAR␥ is mediated through negative cross-talk with Ets-1-dependent transactivation of the TERT promoter.Chromatin immunoprecipitation assays further demonstrated that PPAR␥ 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␥ ligands. In VSMCs overexpressing TERT, the efficacy of PPAR␥ ligands to inhibit cell proliferation is lost, indicating that TERT constitutes an important molecular target for the antiproliferative effects of PPAR␥ ligands. Finally, we demonstrate that telomerase activation during the proliferative response after vascular injury is effectively inhibited by PPAR␥ ligands. These findings provide a previously unrecognized mechanism for the antiproliferative effects of PPAR␥ ligands and support the concept that PPAR␥ ligands may constitute a novel therapeutic approach for the treatment of proliferative cardiovascular diseases.(Circ Res. 2006;98:e50-e59.)Key Words: telomerase Ⅲ peroxisome proliferator-activated receptor Ⅲ vascular smooth muscle cell Ⅲ proliferation P eroxisome proliferator-activated receptor (PPAR) ␥ is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. 1 Synthetic ligands include thiazolidinedione (TZD) PPAR␥ ligands, like rosiglitazone (RSG) or pioglitazone (PIO), which are clinically used as insulin sensitizers in patients with type 2 diabetes. TZD PPAR␥ agonists not only improve insulin resistance in patients with type 2 diabetes but also exert a broad spectrum of pleiotropic vascular effects in vitro and in animal models. 2 PPAR␥ is expressed in macrophages, endothelial cells, and vascular smooth muscle cells (VSMCs) and regulates gene expression of key proteins involved in glucose/lipid metabolism, vascular inflammation, and proliferation. 3 TZD PPAR␥ ligands prevent the development of atherosclerosis and intimal hyperplasia after balloon injury in animal models. 4 -6 Early clinical studies further demonstrate that PPAR␥ ligands prevent the progression of intima/media thickening used as sensitive measurement of atherosclerosis 7,8 and the de...

Spindle cells from AIDS-associated Kaposi's sarcoma lesions express telomerase activity that is enhanced by Kaposi's sarcoma progression factors

“…1), in agreement with previous studies (20). In contrast, primary KSC expressed telomerase activity, albeit to a low level as compared to the EA.hy 926 cell line (Fig.…”

“…For this purpose we employed the TRAP method, which shows the presence of telomerase activity in cellular extracts by a ladder of PCR products differing in size by the addition of TTAGGG repeats (7). Quiescent VSMC were employed as the negative control (20), while the EA.hy 926 cell line was the positive control (18).…”

Telomeres and Telomerase in The Aging Heart

“…(146)(147)(148)(149) In fact, the anti-proliferative, anti-atherosclerosis properties of PPAR-g have been shown to suppress VSMC proliferation, which could be at least in part mediated by its effects on suppression of telomerase activity (proproliferation). This is supported by the findings that PPAR-g activation suppresses telomerase in cultured VSMC (117).…”

“…(104,105,(113)(114)(115) Telomerase has been implicated as an important regulator of VSMC proliferation in vitro, because TERT activation extends the lifespan of cultured VSMCs and, conversely, telomerase inhibition abrogates VSMC proliferation in a dose-dependent manner. (98,99,116) Regulation of VSMC proliferation by targeting telomerase activity appears to be independent of telomere length, because VSMC growth arrest occurs early after telomerase inhibition (98,117) and telomerase expression alone is capable of rescuing the senescent phenotype of human plaque VSMCs despite short telomeres. (118) A role of telomerase on the control of VSMC growth has been also proposed in vivo.…”

Anti-tumor effects of prostaglandin D2 and its metabolites, 15-deoxy-Δ12, 14-PGJ2, by peroxisome proliferator-activated receptor (PPAR) γ-dependent and -independent pathways.

“…15d-PGJ 2 suppresses c-Myc mRNA expression, enhances Sp 1 protein degradation via the ubiquitin-proteasome pathway and inhibits estrogen receptor (ER) β phosphorylation at serine residues. A series of these event is followed by transcriptional repression on the TERT gene 13) , and the induction of apoptosis in the colon cancer cells 14) .…”