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

作者：Chong Wei; Li Yongqing; Liu Baoling; Liu Zhengcai; Zhao Ting; Wonsey Diane R; Chen Changmin; Velmahos George C; deMoya Marc A; King David R; Kung Andrew L; Alam Hasan B^*

来源：Journal of Trauma and Acute Care Surgery, 2012, 72(2): 347-353.

DOI：10.1097/TA.0b013e318243d8b2

• Hypoxia
• macrophages
• SAHA
• HIF-1 alpha
• PHD2

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-1 alpha (HIF-1 alpha) controls proinflammatory gene expression in macrophages, we hypothesized that SAHA would attenuate the HIF-1 alpha associated proinflammatory pathway in a hypoxic macrophage model.
METHODS: Mouse macrophages were exposed to hypoxic conditions (0.5% O-2, 10% CO2, and 89.5% N-2) at 37 degrees C in the presence or absence of SAHA (10 mu mol/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-1 alpha, 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 alpha (TNF-alpha), respectively, in the cell culture medium.
RESULTS: Hypoxia significantly increased cellular level of HIF-1 alpha (1 hour and 4 hours), gene transcription of iNOS (4 hours and 8 hours), iNOS protein (8 hours), NO production (8 hours), and TNF-alpha 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-1 alpha, at 1 hour.
CONCLUSIONS: Treatment with SAHA attenuates hypoxia-HIF-1 alpha-inflammatory pathway in macrophages and suppresses hypoxia-induced release of proinflammatory NO and TNF-alpha. SAHA also causes an early increase in cellular PHD2, which provides, at least in part, a new explanation for the decrease in the HIF-1 alpha protein levels. (J Trauma. 2012; 72: 347-354.

• 出版日期2012-2
• 单位中国医科大学