Anti-inflammatory properties of histone deacetylase inhibitors: a mechanistic study. J Trauma Acute Care Surg 2012 Feb;72(2):347-53; discussion 353-4
Date
02/14/2012Pubmed ID
22327976Pubmed Central ID
PMC3782098DOI
10.1097/TA.0b013e318243d8b2Scopus ID
2-s2.0-84864544598 (requires institutional sign-in at Scopus site) 28 CitationsAbstract
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.
Author List
Chong W, Li Y, Liu B, Liu Z, Zhao T, Wonsey DR, Chen C, Velmahos GC, deMoya MA, King DR, Kung AL, Alam HBAuthor
Marc Anthony De Moya MD Chief, Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnti-Inflammatory Agents
Blotting, Western
Cell Hypoxia
Cells, Cultured
Colorimetry
Enzyme-Linked Immunosorbent Assay
Histone Deacetylase Inhibitors
Hydroxamic Acids
Macrophages
Mice
Nitric Oxide
Nitric Oxide Synthase Type II
RNA
Real-Time Polymerase Chain Reaction
Shock, Hemorrhagic
Tumor Necrosis Factor-alpha
