Abstract W P202: Sex Differences in Transforming Growth Factor B Activated Kinase-1 Signaling Following Experimental Stroke

Introduction: Evidence suggests that post-stroke inflammation and outcome is influenced by sex, yet the mechanistic processes behind these disparities remain largely unknown. Studies have shown that ischemic damage following experimental stroke is reduced in young female mice when compared to their male counterparts and that this protective effect can be diminished by ovariectomy (OVX). TGF-B activated kinase (TAK-1) is an important mediator in inflammatory signaling. TAK decreases following cerebral ischemia and inhibition of TAK reduces infarct size following experimental stroke. TAB2 is an activating binding partner that binds to TAK-1 following stimulation, allowing TAK-1 auto-phosphorylation and activation of the p38/MAPK and JNK inflammatory pathways. Post-stroke regulation of TAK levels and activation may contribute to the ischemic resistance seen in females. Hypothesis: We hypothesized that female mice would have a greater decrease in TAK1 and activated p-TAK1 than their male counterparts following experimental stroke. Methods: Male, intact female and ovariectomized female (OVX) mice were subjected to 90-minute middle cerebral artery occlusion (MCAO) and sacrificed at 24 hours post-stroke. Protein levels of TAK-1, TAB2, pTAK and JNK were examined by Western Blot. Results: TAK and pTAK levels were reduced following stroke in female, male and OVX mice. Baseline levels of both TAK1 and pTAK were lower in female mice and the loss of TAK, pTAK and TAB2 following stroke was more dramatic. JNK levels were lower in female mice than in male mice at baseline (p<.05) and following stroke (p<.01), while the OVX females exhibited intermediate JNK. Conclusions: Female mice exhibit lower baseline JNK levels and do not demonstrate a stroke-induced increase in JNK, indicating a protective resistance against stroke-induced inflammation. The dramatic loss of TAB2 in females results in less binding and activation of TAK, reducing inflammation and conferring neuro-protection. OVX mice showed an intermediate phenotype, indicating that estrogen may play a role in TAK regulation following stroke.