title: Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria.
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.
authors.forename: Julio
authors.initials: J
authors.lastname: Gallego-Delgado
authors.forename: Upal
authors.initials: U
authors.lastname: Basu-Roy
authors.forename: Maureen
authors.initials: M
authors.lastname: Ty
authors.forename: Matilde
authors.initials: M
authors.lastname: Alique
authors.forename: Cristina
authors.initials: C
authors.lastname: Fernandez-Arias
authors.forename: Alexandru
authors.initials: A
authors.lastname: Movila
authors.forename: Pollyanna
authors.initials: P
authors.lastname: Gomes
authors.forename: Ada
authors.initials: A
authors.lastname: Weinstock
authors.forename: Wenyue
authors.initials: W
authors.lastname: Xu
authors.forename: Innocent
authors.initials: I
authors.lastname: Edagha
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Wassmer
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez
mesh_terms: D021581:Active Transport, Cell Nucleus; D000962:Antimalarials / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001921:Brain / Q000098:blood supply / Q000469:parasitology; D002199:Capillary Permeability; D002448:Cell Adhesion; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000469:parasitology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000469:parasitology / Q000473:pathology; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D000077405:Irbesartan; D016779:Malaria, Cerebral / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D016778:Malaria, Falciparum / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D055806:Microvessels / Q000473:pathology; D010963:Plasmodium falciparum; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D051176:beta Catenin / Q000502:physiology*
chemical_list: D000962:Antimalarials; D001713:Biphenyl Compounds; C495270:CTNNB1 protein, human; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D051176:beta Catenin; D000077405:Irbesartan