RGD Reference Report - Activation of peroxisome proliferator-activated receptor gamma suppresses telomerase activity in vascular smooth muscle cells. - Rat Genome Database

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Activation of peroxisome proliferator-activated receptor gamma suppresses telomerase activity in vascular smooth muscle cells.

Authors: Ogawa, D  Nomiyama, T  Nakamachi, T  Heywood, EB  Stone, JF  Berger, JP  Law, RE  Bruemmer, D 
Citation: Ogawa D, etal., Circ Res. 2006 Apr 14;98(7):e50-9. Epub 2006 Mar 23.
RGD ID: 1580657
Pubmed: PMID:16556873   (View Abstract at PubMed)
DOI: DOI:10.1161/01.RES.0000218271.93076.c3   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of cell population proliferation  IMP 1580657 RGD 
negative regulation of telomerase activity  IMP 1580657 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pparg  (peroxisome proliferator-activated receptor gamma)

Objects referenced in this article
Gene PPARG peroxisome proliferator activated receptor gamma Homo sapiens
Gene Pparg peroxisome proliferator activated receptor gamma Mus musculus

Additional Information