Abstract
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.
Highlights
Stroke is one of the most serious diseases, and the therapeutic options for stroke patients remain limited to reperfusion with a tissue plasminogen activator or a mechanical catheter device [1,2]
During the acute phase of stroke, A-kinase anchor protein 12 (AKAP12) expression transiently increased in the affected region (Figure 1a)
Western blotting with endothelial fractions from non-ischemic or ischemic regions showed that endothelial-AKAP12 expression increased after stroke (Figure 1b)
Summary
Stroke is one of the most serious diseases, and the therapeutic options for stroke patients remain limited to reperfusion with a tissue plasminogen activator or a mechanical catheter device [1,2]. During the acute phase of stroke, several deleterious cascades are activated, but some signaling pathways may work to suppress these cascades through compensatory responses [5,6]. The research for pro-survival signaling during the acute phase of stroke is still understudied. Some recent pre-clinical studies have highlighted the importance of the roles of AKAP12 in the brain. The blood-brain barrier (BBB) plays similar roles in regulating the passage of molecules between the circulating blood and brain parenchyma [13,14,15]. In this study we used in vitro and in vivo systems to examine the roles of AKAP12 in BBB function during the acute phase of stroke
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