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J Trauma Acute Care Surg. 2012 Feb;72(2):347-53; discussion 353-4. doi: 10.1097/TA.0b013e318243d8b2.

Anti-inflammatory properties of histone deacetylase inhibitors: a mechanistic study.

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Division of Trauma, Emergency Surgery and Surgical Critical Care, Department of Surgery, Massachusetts General Hospital, 165 Cambridge St., Boston, MA 02114, USA.



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.


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.


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.


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.

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