OxLDL causes both epigenetic modification and signaling regulation on the microRNA-29b gene: Novel mechanisms for cardiovascular diseases

Ku Chung Chen, Yi Chu Liao, I. Chung Hsieh, Yung Song Wang, Ching Yu Hu, Suh Hang Hank Juo

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

MicroRNA-29b has been reported to epigenetically regulate proatherogenic genes in response to oxLDL. Since transcription factors and epigenetic regulations are important mechanisms to regulate gene expression, we investigated whether these mechanisms are involved in oxLDL-induced microRNA-29b upregulation. First, we confirmed that microRNA-29b expression was increased in the aorta of mice fed with a high-fat diet, which was consistent with our previous in vitro findings. Next, we found that oxLDL only activated the microRNA-29b-1/microRNA-29a cluster gene on chromosome 7 but not the other distinct microRNA-29b gene located on chromosome 1. Using the promoter reporter assay and chromatin immunoprecipitation, activator protein-1 (AP-1) was shown to bind to the microRNA-29b-1 promoter. We further identified the signaling pathway of LOX-1/Ca 2+/ROS/ERK/c-Fos was involved in oxLDL-mediated microRNA-29b overexpression after treating with the MAPTAM (Ca 2+ chelator), NAC (ROS scavenger), U0126 (ERK inhibitor) and c-Fos (one of the AP-1 proteins) shRNA, respectively. To investigate epigenetic regulations, we found that microRNA-29b promoter contained no CpG islands for DNA methylation. Therefore we investigated whether histone modifications influence microRNA-29b promoter activity. We showed that down-regulation of HDAC1 and the modifications on histone 3 lysine 4 (H3K4) and H3K9 significantly affected microRNA-29b expression. Furthermore, knockdown of c-Fos expression attenuated the effect of oxLDL-induced histone modifications on the microRNA-29b gene expression. Taken together, our data suggest that both transcription factor activation and histone modifications are important regulatory mechanisms of oxLDL-induced atherogenic process. This article is part of a Special Issue entitled OxLDL causes both epigenetic modification and signaling regulation on the microRNA-29b gene: Novel mechanisms for cardiovascular diseases.

Original languageEnglish
Pages (from-to)587-595
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume52
Issue number3
DOIs
Publication statusPublished - Mar 2012
Externally publishedYes

Keywords

  • AP-1
  • Atherosclerosis
  • Histone modification
  • MiR-29b
  • OxLDL

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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