Abstract 18835: The Histone Deacetylase SIRT1 Modulates STAT3 Activity and Prevents De-differentiation and Proliferation of Vascular Smooth Muscle Cells
Background: De-differentiation and proliferation of vascular smooth muscle cells (SMCs) are hallmarks of vasculo-proliferative diseases. Activation of the class III histone deacetylase SIRT1 has been shown to exert protective effects on vascular lesion progression; however, the molecular mechanisms remain incompletely understood. In this study, we tested the hypothesis that SIRT1 exerts specific effects on the differentiation and proliferation of SMCs and investigated the underlying mechanisms.
Methods and Results: SIRT1 expression levels were significantly down-regulated in proliferating human coronary SMCs in vitro and in SMCs following wire-induced neointimal lesion formation in the mouse femoral artery in vivo. Over-expression of SIRT1 using adenoviral vector systems or activation of SIRT1 with resveratrol attenuated proliferation of cultured SMCs in a dose dependant manner. In addition, SIRT1 activation induced a more differentiated phenotype of SMCs, which was accompanied by higher expression levels of multiple cytoskeletal and contractile proteins, as determined by proteomic analysis (MALDI-TOF) and subsequent immune blotting as well as qPCR. In a mouse model of wire-induced injury, over-expression of wild type-SIRT1 but not a deacetylase inactive SIRT1-H355A mutant prevented neointimal formation and significantly reduced SMC proliferation at 3 weeks after dilation (neointima/media ratio: pAd control: 1.94 ± 0.31, pAd-SIRT1-H355A 2.04 ± 0.24, pAd-SIRT1-WT 0.56 ± 0.49, n=8, P<0.05). A gene microarray analysis identified STAT3 dependent target genes to be strongly regulated in response to changes in SIRT1 expression levels and SIRT1 activity. Using immunoprecipitation analysis, we confirmed a direct interaction of SIRT1 with the transcription factor STAT3. Mechanistically, deacetylation of STAT3 by SIRT1 significantly prevented transcription of cyclinD1 and survivin in activated SMCs.
Conclusion: These data provide evidence that activation of SIRT1 prevents STAT3 signaling in SMCs and holds promise as an excellent therapeutic strategy to target vasculo-proliferative diseases.
- © 2012 by American Heart Association, Inc.