Heat shock protein (hsp) 90 inhibition attenuates NF-kB activation and blocks inflammation. However, the precise mechanism of NF-kB regulation by hsp90 in the endothelium is not clear. We investigated the mechanisms of hsp90 inhibition by 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) on NF-kB activation by LPS in primary human lung microvascular endothelial cells. Transcriptional activation of NF-kB was measured by luciferase reporter assay, gene expression by real-time RT-PCR, DNA binding of transcription factors by chromatin immunoprecipitation assay, protein-protein interaction by coimmunoprecipitation/immunoblotting, histone deacetylase (HDAC)/histone acetyltransferase enzyme activity by fluorometry, and nucleosome eviction by partial microccocal DNase digestion. In human lung microvascular endothelial cells, 17-AAG-induced degradation of IKBa was accomplished regardless of the phosphorylation/ubiquitination state of the protein. Hence, 17-AAG did not block LPS-induced NF-kB nuclear translocation and DNA binding activity. Instead, 17-AAG blocked the recruitment of the coactivator, cAMP response element binding protein binding protein, and prevented the assembly of a transcriptionally competent RNA polymerase II complex at the kB elements of the IKBa (an NFkB-responsive gene) promoter. The effect of LPS on IKBa mRNA expression was associated with rapid deacetylation of histone-H3(Lys9) and a dramatic down-regulation of core histone H3 binding. Even though treatment with an HDAC inhibitor produced the same effect as hsp90 inhibition, the effect of 17-AAG was independent of HDAC. We conclude that hsp90 inhibition attenuates NF-kB transcriptional activation by preventing coactivator recruitment and nucleosome eviction from the target promoter in human lung endothelial cells.Keywords: human lung microvascular endothelial cells; heat shock protein 90 inhibitor; LPS; NF-kB; cAMP response element binding protein binding protein
Clinical RelevanceNF-kB is a master regulator of inflammation. We report on a new mechanism regulating NF-kB activity that could reveal new targets for the management of acute lung injury/acute respiratory distress syndrome and other pulmonary inflammatory disease.
We retrospectively reviewed the incidence rate of clinical postoperative deep vein thrombosis and/or pulmonary embolism in 1703 patients undergoing initial craniotomy for meningioma, glioma, or cerebral metastasis. The incidence rate of clinical thromboembolic complications was 1.59% for all tumor groups within the first 4 weeks of surgery. Patients undergoing surgery for meningiomas had a statistically significant increased risk of thromboembolism despite fewer overall perioperative risk factors, when compared with the other tumor groups. The tumor-specific incidence rates of deep vein thrombosis and/or pulmonary embolism for meningioma, glioma, and metastasis were 3.09%, 0.97%, and 1.03%, respectively. Whether this difference was a result of increased surgical time or an inherent property of meningiomas could not be ascertained.
Direct visualization of the DDR as well as precise evaluation of paraclinoid aneurysm location with high-resolution 3-T MRI is possible. This study shows that high-resolution 3-T MRI is an important means to determine the appropriate management for patients with paraclinoid aneurysms.
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