Neuron-Specific Tumor Necrosis Factor Receptor-Associated Factor 3 Is a Central Regulator of Neuronal Death in Acute Ischemic Stroke [Nervous System]

Neuronal death after ischemic stroke involves multiple pathophysiological events, as well as a complex molecular mechanism. Inhibiting a single therapeutic target that is involved in several ischemic signaling cascades may be a promising strategy for stroke management. Here, we report the versatile biological roles of tumor necrosis factor receptor–associated factor 3 (TRAF3) in ischemic stroke. Using several genetically manipulated mouse strains, we also demonstrated that TRAF3 inhibition can be neuroprotective. TRAF3 expression, which is robustly induced in response to ischemia/reperfusion (I/R) injury, was detected in neurons. Overexpression of TRAF3 in neurons led to aggravated neuronal loss and enlarged infarcts; these effects were reversed in TRAF3-knockout mice. Neuronal TRAF3 also contributed to c-Jun kinase–, nuclear factor B– and Rac-1–induced neuronal death, inflammation, and oxidative stress. Mechanistically, we showed that TRAF3 interacts with transforming growth factor-β–activated kinase 1 (TAK1) and potentiates phosphorylation and activation of TAK1. Phosphorylated TAK1 sequentially initiated activation of nuclear factor B, Rac-1/NADPH oxidase, and c-Jun kinase/c-Jun signaling cascades. Using a combination of adenoviruses encoding dominant-negative TAK1 and the TAK1 inhibitor 5Z-7-oxozeaenol, we demonstrated that the TRAF3-mediated activation of ischemic cascades was TAK1-dependent. More importantly, the adverse phenotypes obs...

Source: Hypertension - August 12, 2015 Category: Cardiology Authors: Gong, J., Li, Z.-Z., Guo, S., Zhang, X.-J., Zhang, P., Zhao, G.-N., Gao, L., Zhang, Y., Zheng, A., Zhang, X.-F., Xiang, M., Li, H. Tags: Apoptosis, Ischemic biology - basic studies, Acute Cerebral Infarction, Oxidant stress Nervous System Source Type: research