Anti-inflammatory properties of histone deacetylase inhibitors: A mechanistic study

Wei Chong, Yongqing Li, Baoling Liu, Zhengcai Liu, Ting Zhao, Diane R. Wonsey, Changmin Chen, George C. Velmahos, Marc A. DeMoya, David R. King, Andrew L. Kung, Hasan B. Alam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

BACKGROUND: We have demonstrated that postshock administration of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, can significantly improve early survival in a highly lethal model of hemorrhagic shock. As the primary insult in hemorrhagic shock is cellular hypoxia, and transcription factor hypoxia-inducible factor-1α (HIF-1α) controls proinflammatory gene expression in macrophages, we hypothesized that SAHA would attenuate the HIF-1α associated proinflammatory pathway in a hypoxic macrophage model. METHODS: Mouse macrophages were exposed to hypoxic conditions (0.5% O2, 10% CO2, and 89.5% N2) at 37°C in the presence or absence of SAHA (10 μmol/L). The cells and culture medium were harvested at 1 hour, 4 hours, and 8 hours. Sham (no hypoxia, no SAHA) served as a control. Western blots were performed to assess protein levels of prolyl hydroxylase 2 (PHD2), HIF-1α, and inducible nitric oxide synthase (iNOS) in the cells. Colorimetric biochemical assay and enzyme-linked immunosorbent assay were used to analyze the release of nitric oxide (NO) and secretion of tumor necrosis factor α (TNF-α), respectively, in the cell culture medium. RESULTS: Hypoxia significantly increased cellular level of HIF-1α (1 hour and 4 hours), gene transcription of iNOS (4 hours and 8 hours), iNOS protein (8 hours), NO production (8 hours), and TNF-α secretion (4 hours and 8 hours). SAHA treatment attenuated all of the above hypoxia-induced alterations in the macrophages. In addition, SAHA treatment significantly increased cellular level of PHD2, one of the upstream negative regulators of HIF-1α, at 1 hour. CONCLUSIONS: Treatment with SAHA attenuates hypoxia-HIF-1α-inflammatory pathway in macrophages and suppresses hypoxia-induced release of proinflammatory NO and TNF-α. SAHA also causes an early increase in cellular PHD2, which provides, at least in part, a new explanation for the decrease in the HIF-1α protein levels.

Original languageEnglish (US)
Pages (from-to)347-354
Number of pages8
JournalJournal of Trauma and Acute Care Surgery
Volume72
Issue number2
DOIs
StatePublished - Feb 2012
Externally publishedYes

Keywords

  • HIF-1α
  • Hypoxia
  • Macrophages
  • PHD2
  • SAHA

ASJC Scopus subject areas

  • Surgery
  • Critical Care and Intensive Care Medicine

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