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Biochim Biophys Acta. 2015 Jun;1849(6):665-76. doi: 10.1016/j.bbagrm.2015.03.001. Epub 2015 Mar 10.

A2b adenosine signaling represses CIITA transcription via an epigenetic mechanism in vascular smooth muscle cells.

Author information

1
Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, China; Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, China.
2
Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, China; Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China.
3
Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, China.
4
Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
5
Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, China.
6
Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, China. Electronic address: hwangnjmu@gmail.com.
7
Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, China. Electronic address: wpxienjmu@gmail.com.
8
Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, China. Electronic address: yjxu2014@gmail.com.

Abstract

Chronic inflammation plays a major role in the pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMC), by expressing and presenting major histocompatibility complex II (MHC II) molecules, help recruit T lymphocyte and initiate the inflammatory response within the vasculature. We have previously shown that VSMCs isolated from mice with deficient adenosine A2b receptor (A2b-null) exhibit higher expression of class II transactivator (CIITA), the master regulator of MHC II transcription, compared to wild type littermates. Here we report that activation of A2b adenosine signaling suppresses CIITA expression in human aortic smooth muscle cells. Down-regulation of CIITA expression was largely attributable to transcriptional repression of type III and IV promoters. Chromatin immunoprecipitation (ChIP) analyses revealed that A2b signaling repressed CIITA transcription by attenuating specific histone modifications on the CIITA promoters in a STAT1-dependent manner. STAT1 interacted with PCAF/GCN5, histone H3K9 acetyltransferases, and WDR5, a key component of the mammalian H3K4 methyltransferase complex, to activate CIITA transcription. A2b signaling prevented recruitment of PCAF/GCN5 and WDR5 to the CIITA promoters in a STAT1-dependent manner. In conclusion, our data suggest that adenosine A2b signaling represses CIITA transcription in VSMCs by manipulating the interaction between STAT1 and the epigenetic machinery.

KEYWORDS:

Adenosine A2b signaling; CIITA transcription; PCAF/GCN5; STAT1; VSMC; WDR5

PMID:
25765819
DOI:
10.1016/j.bbagrm.2015.03.001
[Indexed for MEDLINE]

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