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Title: SIRT1 deacetylates RFX5 and antagonizes repression of collagen type I (COL1A2) transcription in smooth muscle cells

Abstract

Highlights: Black-Right-Pointing-Pointer SIRT1 interacts with and deacetylates RFX5. Black-Right-Pointing-Pointer SIRT1 activation attenuates whereas SIRT1 inhibition enhances collagen repression by RFX5 in vascular smooth muscle cells. Black-Right-Pointing-Pointer SIRT1 promotes cytoplasmic localization and proteasomal degradation of RFX5 and cripples promoter recruitment of RFX5. Black-Right-Pointing-Pointer IFN-{gamma} represses SIRT1 expression in vascular smooth muscle cells. Black-Right-Pointing-Pointer SIRT1 agonist alleviates collagen repression by IFN-{gamma} in vascular smooth muscle cells. -- Abstract: 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 enhancesmore » 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-{gamma} 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.« less

Authors:
 [1];  [2]; ; ;  [3];  [4];  [1];  [1];  [3]
  1. Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University (China)
  2. (China)
  3. Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University (China)
  4. Jiangsu Jiankang Vocational Institute (China)
Publication Date:
OSTI Identifier:
22210332
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 428; Journal Issue: 2; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACETYLATION; COLLAGEN; INFLAMMATION; INHIBITION; MUSCLES; NAD; PROMOTERS; TRANSCRIPTION

Citation Formats

Xia, Jun, Department of Respiratory Medicine, Jiangsu Provincial Hospital of Chinese Traditional Medicine, Wu, Xiaoyan, Yang, Yuyu, Zhao, Yuhao, Fang, Mingming, Xie, Weiping, E-mail: wpxienjmu@gmail.com, Wang, Hong, E-mail: hwangnjmu@gmail.com, and Xu, Yong. SIRT1 deacetylates RFX5 and antagonizes repression of collagen type I (COL1A2) transcription in smooth muscle cells. United States: N. p., 2012. Web. doi:10.1016/J.BBRC.2012.10.043.
Xia, Jun, Department of Respiratory Medicine, Jiangsu Provincial Hospital of Chinese Traditional Medicine, Wu, Xiaoyan, Yang, Yuyu, Zhao, Yuhao, Fang, Mingming, Xie, Weiping, E-mail: wpxienjmu@gmail.com, Wang, Hong, E-mail: hwangnjmu@gmail.com, & Xu, Yong. SIRT1 deacetylates RFX5 and antagonizes repression of collagen type I (COL1A2) transcription in smooth muscle cells. United States. doi:10.1016/J.BBRC.2012.10.043.
Xia, Jun, Department of Respiratory Medicine, Jiangsu Provincial Hospital of Chinese Traditional Medicine, Wu, Xiaoyan, Yang, Yuyu, Zhao, Yuhao, Fang, Mingming, Xie, Weiping, E-mail: wpxienjmu@gmail.com, Wang, Hong, E-mail: hwangnjmu@gmail.com, and Xu, Yong. Fri . "SIRT1 deacetylates RFX5 and antagonizes repression of collagen type I (COL1A2) transcription in smooth muscle cells". United States. doi:10.1016/J.BBRC.2012.10.043.
@article{osti_22210332,
title = {SIRT1 deacetylates RFX5 and antagonizes repression of collagen type I (COL1A2) transcription in smooth muscle cells},
author = {Xia, Jun and Department of Respiratory Medicine, Jiangsu Provincial Hospital of Chinese Traditional Medicine and Wu, Xiaoyan and Yang, Yuyu and Zhao, Yuhao and Fang, Mingming and Xie, Weiping, E-mail: wpxienjmu@gmail.com and Wang, Hong, E-mail: hwangnjmu@gmail.com and Xu, Yong},
abstractNote = {Highlights: Black-Right-Pointing-Pointer SIRT1 interacts with and deacetylates RFX5. Black-Right-Pointing-Pointer SIRT1 activation attenuates whereas SIRT1 inhibition enhances collagen repression by RFX5 in vascular smooth muscle cells. Black-Right-Pointing-Pointer SIRT1 promotes cytoplasmic localization and proteasomal degradation of RFX5 and cripples promoter recruitment of RFX5. Black-Right-Pointing-Pointer IFN-{gamma} represses SIRT1 expression in vascular smooth muscle cells. Black-Right-Pointing-Pointer SIRT1 agonist alleviates collagen repression by IFN-{gamma} in vascular smooth muscle cells. -- Abstract: 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-{gamma} 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.},
doi = {10.1016/J.BBRC.2012.10.043},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 2,
volume = 428,
place = {United States},
year = {2012},
month = {11}
}