Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria
American Society for Clinical Investigation
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.
Cerebral malaria , Brain endothelial integrity , Endothelial disruptions , Malaria-associated deaths , Antimalarial drugs
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
© 2016, The American Society for Clinical Investigation.