Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria
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Published Version
Date
2016-09-19
Authors
Gallego-Delgado, Julio
Basu-Roy, Upal
Ty, Maureen
Alique, Matilde
Fernandez-Arias, Cristina
Movila, Alexandru
Gomes, Pollyanna
Weinstock, Ada
Xu, Wenyue
Edagha, Innocent
Journal Title
Journal ISSN
Volume Title
Publisher
American Society for Clinical Investigation
Published Version
Abstract
Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum–infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter–endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin–induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC–induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised.
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Keywords
Cerebral malaria , Brain endothelial integrity , Endothelial disruptions , Malaria-associated deaths , Antimalarial drugs
Citation
Gallego-Delgado, J., Basu-Roy, U., Ty, M., Alique, M., Fernandez-Arias, C., Movila, A., Gomes, P., Weinstock, A., Xu, W., Edagha, I., Wassmer, S. C., Walther, T., Ruiz-Ortega, M. & Rodriguez, A. (2016) ‘Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria’, The Journal of Clinical Investigation, 126. doi: 10.1172/JCI87306
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© 2016, The American Society for Clinical Investigation.