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Expression of CYP 4A ω-hydroxylase and formation of 20-hydroxyeicosatetreanoic acid (20-HETE) in cultured rat brain astrocytes. Prostaglandins Other Lipid Mediat 2016 07;124:16-26

Date

05/14/2016

Pubmed ID

27174801

Pubmed Central ID

PMC5287377

DOI

10.1016/j.prostaglandins.2016.04.003

Scopus ID

2-s2.0-84973896991   16 Citations

Abstract

Astrocytes secrete vasodilator and vasoconstrictor factors via end feet processes, altering blood flow to meet neuronal metabolic demand. Compared to what is known about the ability of astrocytes to release factors that dilate local cerebral vasculature, very little is known regarding the source and identity of astrocyte derived constricting factors. The present study investigated if astrocytes express CYP 4A ω-hydroxylase and metabolize arachidonic acid (AA) to 20-hydroxyeicotetraenoic acid (20-HETE) that regulates KCa channel activity in astrocytes and cerebral arterial myocyte contractility. Here we report that cultured astrocytes express CYP 4A2/3 ω-hydroxylase mRNA and CYP 4A protein and produce 20-HETE and the CYP epoxygenase metabolites epoxyeicosatrienoic acids (EETs) when incubated with AA. The production of 20-HETE and EETs was enhanced following stimulation of metabotropic glutamate receptors (mGluR) on the astrocytes. Exogenous application of 20-HETE attenuated, whereas inhibition of 20-HETE production with HET-0016 increased the open state probabilities (NPo) of 71pS and 161pS KCa single-channel currents recorded from astrocytes. Exposure of isolated cerebral arterial myocytes to conditioned media from cultured astrocytes caused shortening of the length of freshly isolated cerebral arterial myocytes that was not evident following inhibition of astrocyte 20-HETE synthesis and action. These findings suggest that astrocytes not only release vasodilator EETs in response to mGluR stimulation but also synthetize and release the cerebral arterial myocyte constrictor 20-HETE that also functions as an endogenous inhibitor of the activity of two types of KCa channel currents found in astrocytes.

Author List

Gebremedhin D, Zhang DX, Carver KA, Rau N, Rarick KR, Roman RJ, Harder DR

Authors

Kevin Richard Rarick PhD Assistant Professor in the Pediatrics department at Medical College of Wisconsin
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Arachidonic Acid
Astrocytes
Brain
Cerebrovascular Circulation
Cytochrome P-450 Enzyme System
Gene Expression Regulation, Enzymologic
Hydroxyeicosatetraenoic Acids
Muscle, Smooth, Vascular
Rats
Receptors, Metabotropic Glutamate
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a