title: Role of cAMP-dependent protein kinase A activity in low-dose endothelial monocyte-activating polypeptide-II-induced opening of blood-tumor barrier.
abstract: Our previous studies demonstrated that low-dose endothelial monocyte-activating polypeptide-II (EMAP-II) can selectively increase the permeability of blood-tumor barrier (BTB). In addition, low-dose EMAP-II significantly decreases the cyclic adenosine monophosphate (cAMP) concentration and the protein kinase A (PKA) expression level in tumor tissues in the rat C6 glioma model. In this study, an in vitro BTB model was used to investigate the potential role of cAMP/PKA signaling cascade in EMAP-II-induced BTB hyperpermeability. Our data revealed that low-dose EMAP-II (0.05 nM) induced a significant decrease in total intracellular cAMP concentration and PKA activity in rat brain microvascular endothelial cells (RBMECs). Pretreatment with forskolin to increase intracellular cAMP nearly completely blocked the EMAP-II-induced decrease in transendothelial electric resistance and increase in horseradish peroxidase flux across the BTB. Similar pretreatment completely prevented the EMAP-II-induced changes in RhoA/Rho kinase activity, expression and distribution of tight junction-associated protein ZO-1, and myosin light chain phosphorylation, as well as actin cytoskeleton arrangement in RBMECs. Pretreatment with 6Bnz-cAMP to activate PKA significantly attenuated these EMAP-II-induced alterations in RBMECs. In summary, our present study demonstrates that the cAMP/PKA signaling cascade works as a crucial signaling pathway in EMAP-II-induced BTB hyperpermeability.
authors.affiliation: Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, 110004, Liaoning Province, People's Republic of China, cmulizhen1971@163.com.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Xiao-bai
authors.initials: XB
authors.lastname: Liu
authors.forename: Yun-hui
authors.initials: YH
authors.lastname: Liu
authors.forename: Yi-xue
authors.initials: YX
authors.lastname: Xue
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Li-bo
authors.initials: LB
authors.lastname: Liu
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001932:Brain Neoplasms / Q000098:blood supply*; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D055806:Microvessels / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D062725:Tight Junction Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C485473:Eml2 protein, rat; D008869:Microtubule-Associated Proteins; D062725:Tight Junction Proteins; D000242:Cyclic AMP; D054460:rho-Associated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D020742:rhoA GTP-Binding Protein