SIRT1 deacetylates RFX5 and antagonizes repression of collagen type I (COL1A2) transcription in smooth muscle cells.
Decreased expression of collagen by vascular smooth muscle cells (SMCs) within the atherosclerotic plaque contributes to the thinning of the fibrous cap and poses a great threat to plaque rupture. Elucidation of the mechanism underlying repressed collagen type I (COL1A2) gene would potentially provide novel solutions that can prevent rupture-induced complications. We have previously shown that regulatory factor for X-box (RFX5) binds to the COL1A2 transcription start site and represses its transcription. Here we report that SIRT1, an NAD-dependent, class III deacetylase, forms a complex with RFX5. Over-expression of SIRT1 or NAMPT, which synthesizes NAD+ to activate SIRT1, or treatment with the SIRT1 agonist resveratrol decreases RFX5 acetylation and disrupts repression of the COL1A2 promoter activity by RFX5. On the contrary, knockdown of SIRT1 or treatment with SIRT1 inhibitors induces RFX5 acetylation and enhances the repression of collagen transcription. SIRT1 antagonizes RFX5 activity by promoting its nuclear expulsion and proteasomal degradation hence dampening its binding to the COL1A2 promoter. The pro-inflammatory cytokine IFN-γ represses COL1A2 transcription by down-regulating SIRT1 expression in SMCs. Therefore, our data have identified as novel pathway whereby SIRT1 maintains collagen synthesis in SMCs by modulating RFX5 activity.
Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, China.
Jun
J
Xia
Xiaoyan
X
Wu
Yuyu
Y
Yang
Yuhao
Y
Zhao
Mingming
M
Fang
Weiping
W
Xie
Hong
H
Wang
Yong
Y
Xu
D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D024042:Collagen Type I; D004268:DNA-Binding Proteins; C093524:RFX5 protein, human; D000071701:Regulatory Factor X Transcription Factors; D016899:Interferon-beta; D046988:Proteasome Endopeptidase Complex; C447939:SIRT1 protein, human; D056564:Sirtuin 1