Abstract
The adenosine triphosphate-binding cassette transporters ABCB1 and ABCC1 show coordinated changes in abundance at the luminal and abluminal membranes of ischemic cerebral capillaries that impede the brain access of pharmacological compounds. We found that apolipoprotein E (ApoE) was present on ischemic microvessels but not contralateral controls. ApoE signaled through ApoE receptor-2 (ApoER2), which was constitutively expressed on brain microvessels, to decrease c-Jun amino-terminal kinase 1 and 2 and c-Jun activities. ApoE regulated the postischemic abundance of ABCB1 and ABCC1, thereby controlling drug accumulation in the ischemic brain. Our data suggest that inhibition of ApoE signaling may enable improved delivery of drugs to the brain.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism*
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Animals
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Apolipoproteins E / genetics
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Apolipoproteins E / metabolism*
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Brain Ischemia / genetics
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Brain Ischemia / metabolism*
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Capillaries / metabolism
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Cerebellum / blood supply
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Cerebellum / metabolism
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Gene Expression Regulation / genetics
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Humans
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LDL-Receptor Related Proteins
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Mice
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Mice, Knockout
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Multidrug Resistance-Associated Proteins / genetics
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Multidrug Resistance-Associated Proteins / metabolism*
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Receptors, Lipoprotein / biosynthesis*
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Receptors, Lipoprotein / genetics
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Signal Transduction*
Substances
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP-Binding Cassette Transporters
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Apolipoproteins E
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LDL-Receptor Related Proteins
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Multidrug Resistance-Associated Proteins
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Receptors, Lipoprotein
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low density lipoprotein receptor-related protein 8
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Abcb1b protein, mouse
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multidrug resistance-associated protein 1