AKAP12 Supports Blood-Brain Barrier Integrity against Ischemic Stroke.

A-kinase anchor protein 12 (AKAP12) is a scaffolding protein that associates with intracellular molecules to regulate multiple signal transductions. Although the roles of AKAP12 in the central nervous system are still relatively understudied, it was previously shown that AKAP12 regulates blood-retinal barrier formation. In this study, we asked whether AKAP12 also supports the function and integrity of the blood-brain barrier (BBB). In a mouse model of focal ischemia, the expression level of AKAP12 in cerebral endothelial cells was upregulated during the acute phase of stroke. Also, in cultured cerebral endothelial cells, oxygen-glucose deprivation induced the upregulation of AKAP12. When AKAP12 expression was suppressed by an siRNA approach in cultured endothelial cells, endothelial permeability was increased along with the dysregulation of ZO-1/Claudin 5 expression. In addition, the loss of AKAP12 expression caused an upregulation/activation of the Rho kinase pathway, and treatment of Rho kinase inhibitor Y-27632 mitigated the increase of endothelial permeability in AKAP12-deficient endothelial cell cultures. These in vitro findings were confirmed by our in vivo experiments using Akap12 knockout mice. Compared to wild-type mice, Akap12 knockout mice showed a larger extent of BBB damage after stroke. However, the inhibition of rho kinase by Y-27632 tightened the BBB in Akap12 knockout mice. These data may suggest that endogenous AKAP12 works to alleviate the damage and dysfunction of the BBB caused by ischemic stress. Therefore, the AKAP12-rho-kinase signaling pathway represents a novel therapeutic target for stroke.

Cytokine gene polymorphisms in recurrent spontaneous abortions: a comprehensive review.

PROBLEM: Cytokine gene polymorphism studies in women with recurrent spontaneous abortion (RSA) are reviewed to provide comprehensive understanding and a direction for the future investigation. METHOD OF STUDY: A search of PubMed was made to identify the published data between 2001 and 2007 regarding RSA and cytokine gene polymorphisms. RESULTS: Either allele and/or genotype frequencies of the following polymorphisms were reported to be significantly different between women with RSA and controls: IFN-gamma +874A-->T, TA (P = 0.01), AA (P = 0.04); IL-6, -634C-->G CG/GG (P = 0.026); IL-10, -592C-->A CC (P = 0.016); IL-1B -511C (P = 0.035), -31T (P = 0.029); IL-1RA, IL1RN*2 (P = 0.002), and IL1RN*3 (P = 0.002). None of these studies was repeatedly reported by others to be significantly different. Among these, four cytokine polymorphisms (IFN-gamma, +874A-->T; IL-1B -511C; IL-1RA, IL1RN*2, IL1RN*3) were refuted by others and rest of them were studied once. CONCLUSION: Multiple cytokine polymorphisms were reported to be associated with RSA. However, a majority of studies were not confirmed by other investigators or refuted by others. Inconsistent study results might be related to: (i) the production of these cytokines is partly under genetic controls and other factors affect cytokine levels; (ii) ethnic background, environmental factors, and selection criteria for study populations are different and (iii) the possibilities exist that multiple cytokine gene polymorphisms or other genes in linkage disequilibrium may play a role in RSA.