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 October 3, 2016; First 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 3

Rupture of P. falciparum schizonts, but not cytoadhesion, is required to induce the HBMEC monolayer disruption and migration of β-catenin.

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Rupture of P. falciparum schizonts, but not cytoadhesion, is required to...
(A and B) Monolayers of HBMECs were incubated without parasites (Control) or with D10-PfCDPK5-DDTM P. falciparum schizonts (1:40) in the absence (–) or presence (+) of Shield-1 (Shld). The presence of Shield-1 allows conditionally CDPK5-deficient arrested schizonts to rupture (18). (C and D) HBMECs were incubated alone, with uninfected RBCs, or with IT4var19 P. falciparum schizonts (1:40) with or without knobs. (E–G) HBMECs were incubated alone, with uninfected RBCs, or with 3D7 P. falciparum schizonts (1:40) under flow conditions (ζ = 1 dyn/cm2). HBMEC immunostaining for β-catenin (green), actin (red), and nuclei (blue) is shown in panel E. Scale bar: 30 μm. (H and I) HBMECs were incubated alone or with the culture media of ruptured iRBCs. Results are expressed as average number of HBMECs per microscopic field (n = 10) in A, C, F, and H, and as the quantification of β-catenin fluorescence intensity in the perinuclear and nuclear areas versus IEJs for each cell in 10 microscopic fields in B, D, G, and I. Results are representative of at least 3 independent experiments. Error bars represent ±SEM. *P < 0.05, ***P < 0.001 compared with control. Parametric 2-tailed Student’s t test (H and I) or 1-way ANOVA and Tukey post hoc analysis were applied (A–D, F, and G).