Genetic deletion of calcium/calmodulin-dependent protein kinase kinase β (CaMKK β) or CaMK IV exacerbates stroke outcomes in ovariectomized (OVXed) female mice

BMC Neuroscience

Jun Li²  Louise McCullough¹  Lin Liu² 

[1] Department of Neurology, University of Connecticut Health Center, Farmington, CT, USA;Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, MC3401, Farmington 06030, CT, USA

关键词: Sex differences;    Inflammation;    CaMK IV;    CaMKK β;    Stroke;   

Others  :  1090816
DOI  :  10.1186/s12868-014-0118-2

 received in 2014-06-25, accepted in 2014-10-08,  发布年份 2014

【 摘 要 】

Background

Stroke is the primary cause of long-term disability in the United States. Interestingly, mounting evidence has suggested potential sex differences in the response to stroke treatment in patients as, at least in part, distinct cell death programs may be triggered in females and males following stroke. The NIH has recognized that females are strikingly under-represented in pre-clinical trials. Calcium/calmodulin-dependent protein kinase kinase (CaMKK) is a major kinase that is activated by elevated intracellular calcium. It has recently been suggested that CaMKK and CaMK IV, a downstream target molecule, are neuroprotective in stroke in males. In this study, we examined stroke outcomes in ovariectomized CaMKK β and CaMK IV deficient females. Cell death/survival signaling and inflammatory responses were assessed.

Results

Our results demonstrated that CaMKK β or CaMK IV KO exacerbated both ischemic injury and behavioral deficits in female mice. Genetic deletion of CaMKK β or CaMK IV increased hemorrhagic transformation after stroke, and this was associated with both increased MMP9 activity and loss of the blood brain barrier (BBB) protein collagen IV. Transcriptional inactivation was observed in mice lacking either CaMKK β or CaMK IV, as indicated by reduced levels of phosphorylated cAMP response element-binding protein (p-CREB) and B-cell lymphoma 2 (BCL-2) proteins. Finally, inhibiting this pathway exacerbated the inflammatory response to stroke as CaMKK β or CaMK IV KO mice had increased levels of the pro-inflammatory serum cytokines tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6) after stroke. This suggests that the CaMKK pathway is involved in the immune response to brain injury.

Conclusions

Inhibition of CaMKK signaling exacerbated stroke outcome and increased BBB impairment, transcriptional inactivation and inflammatory responses in females after stroke. Therefore, CaMKK signaling may be a potential target for stroke treatment in both males and females.

【 授权许可】

   
2014 Liu et al.; licensee BioMed Central Ltd.

【 图 表 】

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