Role of ATP synthase alpha subunit in low-dose endothelial monocyte-activating polypeptide-II-induced opening of the blood-tumor barrier

This study was performed to determine whether the a subunit of ATP synthase (alpha-ATP synthase) on brain microvascular endothelial cells (BMECs) serves as the functional target for endothelial monocyte-activating polypeptide-II (EMAP-II)-induced increase in blood-tumor barrier (BIB) permeability. Using a rat CO glioma model, we found that low-dose (80 ng/kg) EMAP-Il significantly decreased the mRNA and protein expression levels of tight junction (TJ)-related proteins claudin-5, occludin, and ZO-1 on BMECs. Meantime. radioimmunity and Western blot assay she-red a significant decrease in the expression levels of cAMP and catalytic subunit of protein kinase A (PKAcs) of tumor tissues. Also, pretreatment with specific a-ATP synthase antibody significantly blocked the effects of EMAP-II on TJ-related proteins, cAMP, and PKAcs. In addition, double immunofluorescence assay identified that EMAP-II was co-localized with a-ATP synthase on BMECs. This in vivo study demonstrated that a subunit of ATP synthase on BMECs serves as the functional target for EMAP-Il selective opening of the BTB, and that cAMP/PKA signaling transduction pathway might be involved in the modulating process. (c) 2010 Elsevier B.V. All rights reserved.