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The PPARalpha/p16INK4a pathway inhibits vascular smooth muscle cell proliferation by repressing cell cycle-dependent telomerase activation.
- Source :
-
Circulation research [Circ Res] 2008 Nov 07; Vol. 103 (10), pp. 1155-63. Date of Electronic Publication: 2008 Sep 25. - Publication Year :
- 2008
-
Abstract
- Peroxisome proliferator-activated receptor (PPAR)alpha, the molecular target for fibrates used to treat dyslipidemia, exerts pleiotropic effects on vascular cells. In vascular smooth muscle cells (VSMCs), we have previously demonstrated that PPARalpha activation suppresses G(1)-->S cell cycle progression by targeting the cyclin-dependent kinase inhibitor p16(INK4a) (p16). In the present study, we demonstrate that this inhibition of VSMC proliferation by PPARalpha is mediated through a p16-dependent suppression of telomerase activity, which has been implicated in key cellular functions including proliferation. PPARalpha activation inhibited mitogen-induced telomerase activity by repressing the catalytic subunit telomerase reverse transcriptase (TERT) through negative cross-talk with an E2F-1-dependent trans-activation of the TERT promoter. This trans-repression involved the recruitment of the retinoblastoma (RB) family proteins p107 and p130 to the TERT promoter resulting in impaired E2F-1 binding, an effect that was dependent on p16. The inhibition of cell proliferation by PPARalpha activation was lost in VSMCs following TERT overexpression or knockdown, pointing to a key role of telomerase as a target for the antiproliferative effects of PPARalpha. Finally, we demonstrate that PPARalpha agonists suppress telomerase activation during the proliferative response following vascular injury, indicating that these findings are applicable in vivo. In concert, these results demonstrate that the antiproliferative effects of PPARalpha in VSMCs depend on the suppression of telomerase activity by targeting the p16/RB/E2F transcriptional cascade.
- Subjects :
- Animals
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p16 genetics
Dyslipidemias enzymology
Dyslipidemias genetics
E2F1 Transcription Factor genetics
E2F1 Transcription Factor metabolism
Enzyme Activation drug effects
Enzyme Activation physiology
Gene Expression Regulation, Enzymologic drug effects
Mice
Mitogens metabolism
Mitogens pharmacology
PPAR alpha agonists
Promoter Regions, Genetic physiology
Rats
Retinoblastoma-Like Protein p107 genetics
Retinoblastoma-Like Protein p107 metabolism
Retinoblastoma-Like Protein p130 genetics
Retinoblastoma-Like Protein p130 metabolism
Telomerase genetics
Transcription, Genetic drug effects
Transcription, Genetic physiology
Cyclin-Dependent Kinase Inhibitor p16 metabolism
G1 Phase physiology
Gene Expression Regulation, Enzymologic physiology
Myocytes, Smooth Muscle enzymology
PPAR alpha metabolism
S Phase physiology
Telomerase biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 103
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 18818403
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.108.186205