HDAC9 promotes brain ischemic injury by provoking IκBα/NF-κB and MAPKs signaling pathways
- Department of Anesthesiology, China Japan Union Hospital of Jilin University, Jilin, 130033 (China)
- Department of Hepatobiliary and Pancreas Surgery, China Japan Union Hospital of Jilin University, Jilin, 130033 (China)
Highlights: • HDAC9 deletion protects against I/R-induced ischemic brain injury in vivo. • HDAC9 ablation down-regulates I/R-induced inflammation in brain of mice. • HDAC9 knockdown alleviates LPS-induced inflammation in BV2 cells partially by MAPKs pathway. Ischemic stroke is an acute cerebrovascular disease due to poor blood flow to the brain. Nevertheless, there is still no effective therapy for it and the pathology contributing to ischemic stroke is not fully understood. Histone Deacetylase 9 (HDAC9) is a class IIa chromatin-modifying enzyme. HDAC9 gene region is a leading risk locus for large artery atherosclerotic stroke. However, the mechanisms linking HDAC9 to ischemic remain elusive. In the study, we attempted to explore HDAC9-associated inflammatory response using the wild type (WT) and HDAC9-knockout (KO) mice with brain ischemic injury. The results indicated that WT mice with ischemia brain exhibited higher expression levels of HDAC9. HDAC9 depletion resulted in a decreased infarct volume and an improved neurological function in mice after ischemic reperfusion (I/R) injury. I/R injury markedly enhanced GFAP and Iba-1 expressions in cortex and HDAC9 knockout significantly reversed this up-regulation. Loss of HDAC9 inhibited the release of inducible NO-synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin 1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and IL-18 in cortex, hippocampus and hypothalamus of mice with I/R injury, which occurred at the transcription levels. Furthermore, the inhibitory actions of HDAC9 deficiency were associated with the down-regulation of phosphorylated-IκBα, phosphorylated-nuclear factor-kappa B (NF-κB), and p-mitogen-activated protein kinases (MAPKs), including phosphorylated-p38, phosphorylated-extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated-c-Jun N-terminal kinase (JNK). Importantly, the in vitro study indicated that HDAC9 inhibition-reduced inflammation and activation of IκBα/NF-κB were restored by promoting MAPKs activity in LPS-stimulated cells. Our findings suggest that HDAC9 inhibition showed neuroprotective effects on ischemic stroke by restraining inflammation, which might help develop new and effective strategies for the therapeutic interventions in ischemic stroke.
- OSTI ID:
- 23105531
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 503, Issue 3; Other Information: Copyright (c) 2018 Published by Elsevier Inc.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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