Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria
Julio Gallego-Delgado, … , Marta Ruiz-Ortega, Ana Rodriguez
Julio Gallego-Delgado, … , Marta Ruiz-Ortega, Ana Rodriguez
Published September 19, 2016
Citation Information: J Clin Invest. 2016;126(10):4016-4029. https://doi.org/10.1172/JCI87306.
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Research Article Infectious disease Vascular biology

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

Julio Gallego-Delgado, Upal Basu-Roy, Maureen Ty, Matilde Alique, Cristina Fernandez-Arias, Alexandru Movila, Pollyanna Gomes, Ada Weinstock, Wenyue Xu, Innocent Edagha, Samuel C. Wassmer, Thomas Walther, Marta Ruiz-Ortega, Ana Rodriguez

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Figure 1

Pf-iRBCs induce a dose-dependent detachment from substrate and disruption of IEJs in HBMECs.

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Pf-iRBCs induce a dose-dependent detachment from substrate and disrupti...
Monolayers of HBMECs were incubated with Pf-iRBCs at the schizont stage or control uninfected RBCs for 18 hours at the indicated ratios of iRBCs to HBMECs or 40:1 for RBCs. (A) Average number of HBMECs per microscopic field (n = 10). (B) PrestoBlue determination of viable attached HBMECs. (C) FACS analysis of attached and detached HBMECs stained with propidium iodide or annexin V. (D) Transendothelial electrical resistance (TEER) for HBMEC monolayers incubated with Pf-iRBCs (blue) or control uninfected RBCs (red) at iRBC/HBMEC ratios of 10:1 (dotted line), 20:1 (dashed line), or 40:1 (continuous line), normalized by TEER of HBMECs alone. Results are the average of 6 independent measurements. Results are representative of at least 3 independent experiments. Error bars represent ±SEM. *P < 0.05, ***P < 0.001 compared with control (1-way ANOVA and Tukey post hoc analysis).