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Activation of peroxisome proliferator-activated receptor gamma suppresses telomerase activity in vascular smooth muscle cells.
- Source :
-
Circulation research [Circ Res] 2006 Apr 14; Vol. 98 (7), pp. e50-9. Date of Electronic Publication: 2006 Mar 23. - Publication Year :
- 2006
-
Abstract
- Activation of the peroxisome proliferator-activated receptor (PPAR) gamma, 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 PPARgamma activation inhibits telomerase activity in VSMCs. Telomerase reverse transcriptase (TERT) confers the catalytic activity of telomerase, and PPARgamma 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 PPARgamma is mediated through negative cross-talk with Ets-1-dependent transactivation of the TERT promoter. Chromatin immunoprecipitation assays further demonstrated that PPARgamma ligands inhibit Ets-1 binding to the TERT promoter, which is mediated at least in part through an inhibition of Ets-1 expression by PPARgamma ligands. In VSMCs overexpressing TERT, the efficacy of PPARgamma ligands to inhibit cell proliferation is lost, indicating that TERT constitutes an important molecular target for the antiproliferative effects of PPARgamma ligands. Finally, we demonstrate that telomerase activation during the proliferative response after vascular injury is effectively inhibited by PPARgamma ligands. These findings provide a previously unrecognized mechanism for the antiproliferative effects of PPARgamma ligands and support the concept that PPARgamma ligands may constitute a novel therapeutic approach for the treatment of proliferative cardiovascular diseases.
- Subjects :
- Animals
Aorta
Base Sequence
Cardiovascular Diseases therapy
Cell Division physiology
Cells, Cultured
DNA Primers
Enzyme Activation
Microscopy, Confocal
Muscle, Smooth, Vascular cytology
Muscle, Smooth, Vascular enzymology
Mutagenesis, Site-Directed
PPAR gamma genetics
Rats
Recombinant Proteins metabolism
Telomerase metabolism
Transfection
Muscle, Smooth, Vascular physiology
PPAR gamma physiology
Telomerase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 98
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 16556873
- Full Text :
- https://doi.org/10.1161/01.RES.0000218271.93076.c3