Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria

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dc.contributor.authorGallego-Delgado, Julio
dc.contributor.authorBasu-Roy, Upal
dc.contributor.authorTy, Maureen
dc.contributor.authorAlique, Matilde
dc.contributor.authorFernandez-Arias, Cristina
dc.contributor.authorMovila, Alexandru
dc.contributor.authorGomes, Pollyanna
dc.contributor.authorWeinstock, Ada
dc.contributor.authorXu, Wenyue
dc.contributor.authorEdagha, Innocent
dc.contributor.authorWassmer, Samuel C.
dc.contributor.authorWalther, Thomas
dc.contributor.authorRuiz-Ortega, Marta
dc.contributor.authorRodriguez, Ana
dc.date.accessioned2016-09-30T14:06:53Z
dc.date.available2016-09-30T14:06:53Z
dc.date.issued2016-09-19
dc.description.abstractCerebral 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.en
dc.description.sponsorshipNational Institutes of Health, (NIH/National Heart, Lung, and Blood Institute (NHLBI) 1R01HL130630, NIH Training Grant 5T32AI007180-30, NIH/National Institute of Allergy and Infectious Diseases U19AI089676-01S10); Dana Foundation Program (Neuroimmunology of Brain Infections and Cancers Grant); Fundacion Española para la Ciencia y la Tecnologia, (mobility program, Ministry of Education of Spain); Red de Investigación Renal (REDinREN; RD12/0021); Comunidad de Madrid (Fibroteam; S2010/BMD-2321)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationGallego-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/JCI87306en
dc.identifier.doi10.1172/JCI87306
dc.identifier.endpage14en
dc.identifier.issn0021-9738
dc.identifier.issn1558-8238
dc.identifier.journaltitleJournal of Clinical Investigationen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/3146
dc.identifier.volume126en
dc.language.isoenen
dc.publisherAmerican Society for Clinical Investigationen
dc.rights© 2016, The American Society for Clinical Investigation.en
dc.subjectCerebral malariaen
dc.subjectBrain endothelial integrityen
dc.subjectEndothelial disruptionsen
dc.subjectMalaria-associated deathsen
dc.subjectAntimalarial drugsen
dc.titleAngiotensin receptors and β-catenin regulate brain endothelial integrity in malariaen
dc.typeArticle (peer-reviewed)en
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