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 6

Modulators of Ang II receptors inhibit experimental cerebral malaria.

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Modulators of Ang II receptors inhibit experimental cerebral malaria. Gr...
Groups of WT or AT2-deficient (AT2–/–, black diamonds) C57BL/6J mice (n = 38 and 9, respectively) were infected with P. berghei ANKA. Starting on the day of infection, WT mice were treated with losartan (in drinking water 10 mg/kg/d; n = 15; triangles) or CGP-42112A (administered through intradermal micropumps 500 ng/min/kg; n = 7; squares). Control mice drinking regular water (n = 7; black circles) or implanted with intradermal micropumps delivering saline (n = 9; gray circles) were used. (A and B) Survival and mean parasitemia. (C–E) Histological sections of the brains of mice were analyzed for the presence (C) and size (D) of hemorrhages. Control group includes mice drinking regular water and implanted with intradermal micropumps delivering saline. Center lines show the medians; box limits indicate the 25th and 75th percentiles as determined by R software; whiskers extend to minimum and maximum values. (E) Representative microscopic fields. Scale bars: 100 μm. Error bars represent ± SEM. *P < 0.05, **P < 0.01 compared with control. Kaplan-Meier and pairwise log rank after Bonferroni correction in A. One-way repeated-measures ANOVA for B. One-way ANOVA for the medians in C and D.