Microvascular Endothelial Cell Death and Rarefaction in the Glucocorticoid-Induced Hypertensive Rat

Microvascular degeneration is an important event in oxygen-induced retinopathy (OIR), a model of retinopathy of prematurity. Because oxidant stress abundantly generates thromboxane A2(TxA2), we tested whether TxA2plays a role in retinal vasoobliteration of OIR and contributes to such vascular degeneration by direct endothelial cytotoxicity. Hyperoxia-induced retinal vasoobliteration in rat pups (80% O2exposure from postnatal days 5–14) was associated with increased TxB2generation and was significantly prevented by TxA2synthase inhibitor CGS-12970 (10 mg · kg−1· day−1) or TxA2-receptor antagonist CGS-22652 (10 mg · kg−1· day−1). TxA2mimetics U-46619 (EC5050 nM) and I-BOP (EC505 nM) caused a time- and concentration-dependent cell death of neuroretinovascular endothelial cells from rats as well as newborn pigs but not of smooth muscle and astroglial cells; other prostanoids did not cause cell death. The peroxidation product 8-iso-PGF2, which is generated in OIR, stimulated TxA2formation by endothelial cells and triggered cell death; these effects were markedly diminished by CGS-12970. TxA2-dependent neuroretinovascular endothelial cell death was mostly by necrosis and to a lesser extent by apoptosis. The data identify an important role for TxA2in vasoobliteration of OIR and unveil a so far unknown function for TxA2in directly triggering neuroretinal microvascular endothelial cell death. These effects of TxA2might participate in other ischemic neurovascular injuries.

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Acanthamoeba castellanii Induces Host Cell Death via a Phosphatidylinositol 3-Kinase-Dependent Mechanism

Infection and Immunity ◽

10.1128/iai.73.5.2704-2708.2005 ◽

2005 ◽

Vol 73 (5) ◽

pp. 2704-2708 ◽

Cited By ~ 70

Author(s):

James Sissons ◽

Kwang Sik Kim ◽

Monique Stins ◽

Samantha Jayasekera ◽

Selwa Alsam ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Death ◽

Endothelial Cell ◽

Acanthamoeba Castellanii ◽

Microvascular Endothelial Cells ◽

Brain Microvascular Endothelial Cells ◽

Phosphatidylinositol 3 Kinase ◽

Endothelial Cell Death ◽

Microvascular Endothelial ◽

Phosphatidylinositol 3

ABSTRACT Granulomatous amoebic encephalitis due to Acanthamoeba castellanii is a serious human infection with fatal consequences, but it is not clear how the circulating amoebae interact with the blood-brain barrier and transmigrate into the central nervous system. We studied the effects of an Acanthamoeba encephalitis isolate belonging to the T1 genotype on human brain microvascular endothelial cells, which constitute the blood-brain barrier. Using an apoptosis-specific enzyme-linked immunosorbent assay, we showed that Acanthamoeba induces programmed cell death in brain microvascular endothelial cells. Next, we observed that Acanthamoeba specifically activates phosphatidylinositol 3-kinase. Acanthamoeba-mediated brain endothelial cell death was abolished using LY294002, a phosphatidylinositol 3-kinase inhibitor. These results were further confirmed using brain microvascular endothelial cells expressing dominant negative forms of phosphatidylinositol 3-kinase. This is the first demonstration that Acanthamoeba-mediated brain microvascular endothelial cell death is dependent on phosphatidylinositol 3-kinase.

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