Malondialdehyde mediates oxidized LDL-induced coronary toxicity through the Akt-FGF2 pathway via DNA methylation

Tzu Ching Yang, Yi Jie Chen, Shwu Fen Chang, Chu Huang Chen, Po Yuan Chang, Shao Chun Lu

研究成果: 雜誌貢獻文章同行評審

26 引文 斯高帕斯(Scopus)

摘要

Background: Oxidized LDL (oxLDL) is involved in the development of atherosclerotic heart disease through a mechanism that is not fully understood. In this study, we examined the role of malondialdehyde (MDA), an important oxidative stress epitope of oxLDL, in mediating coronary endothelial cytotoxicity. Results: Human coronary artery endothelial cells (HCAECs) were treated with oxLDL in the presence or absence of antibody against MDA (anti-MDA) or apoB100 (anti-apoB100). In HCAECs treated with oxLDL (100 μg/ml) alone, DNA synthesis, cell viability, and expression of prosurvival fibroblast growth factor 2 (FGF2) were significantly reduced (P <0.01 vs phosphate buffered saline-treated cells). These inhibitory effects of oxLDL were significantly attenuated in HCAECs cotreated with anti-MDA (0.15 μg/ml; P <0.05 vs oxLDL-treated cells), but not in those cotreated with anti-apoB100. When we tested the effects of a panel of signal transduction modifiers on the signal transduction pathways of MDA in oxLDL-treated HCAECs, we found that MDA-induced cytotoxicity was mediated partly through the Akt pathway. Using a reporter gene assay, we identified an oxLDL-response element in the FGF2 promoter that was responsible for the transcriptional repression of FGF2 by oxLDL. The results of bisulfite genomic DNA sequencing showed that in HCAECs treated with oxLDL, the GC-rich promoter of FGF2 was heavily methylated at cytosine residues, whereas cotreatment with anti-MDA markedly reduced oxLDL-induced FGF2 promoter methylation. Conclusion: OxLDL disrupts the growth and survival of HCAECs through an MDA-dependent pathway involving methylation of the FGF2 promoter and repression of FGF2 transcription. This novel epigenetic mechanism of oxLDL may underlie its atherogenicity in patients with atherosclerotic cardiovascular disease.

原文英語
文章編號11
期刊Journal of Biomedical Science
21
發行號1
DOIs
出版狀態已發佈 - 二月 3 2014

ASJC Scopus subject areas

  • 臨床生物化學
  • 分子生物學
  • 細胞生物學
  • 生物化學(醫學)
  • 內分泌學、糖尿病和代謝
  • 藥學(醫學)

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