Rhythmic expression of cytochrome P450 epoxygenases CYP4x1 and CYP2c11 in the rat brain and vasculature. Am J Physiol Cell Physiol 2014 Dec 01;307(11):C989-98
Date
07/25/2014Pubmed ID
25055826Pubmed Central ID
PMC4254955DOI
10.1152/ajpcell.00401.2013Scopus ID
2-s2.0-84914140128 (requires institutional sign-in at Scopus site) 54 CitationsAbstract
Mammals have circadian variation in blood pressure, heart rate, vascular tone, thrombotic tendency, and cerebral blood flow (CBF). These changes may be in part orchestrated by circadian variation in clock gene expression within cells comprising the vasculature that modulate blood flow (e.g., fibroblasts, cerebral vascular smooth muscle cells, astrocytes, and endothelial cells). However, the downstream mechanisms that underlie circadian changes in blood flow are unknown. Cytochrome P450 epoxygenases (Cyp4x1 and Cyp2c11) are expressed in the brain and vasculature and metabolize arachidonic acid (AA) to form epoxyeicosatrienoic acids (EETs). EETs are released from astrocytes, neurons, and vascular endothelial cells and act as potent vasodilators, increasing blood flow. EETs released in response to increases in neural activity evoke a corresponding increase in blood flow known as the functional hyperemic response. We examine the hypothesis that Cyp2c11 and Cyp4x1 expression and EETs production vary in a circadian manner in the rat brain and cerebral vasculature. RT-PCR revealed circadian/diurnal expression of clock and clock-controlled genes as well as Cyp4x1 and Cyp2c11, within the rat hippocampus, middle cerebral artery, inferior vena cava, hippocampal astrocytes and rat brain microvascular endothelial cells. Astrocyte and endothelial cell culture experiments revealed rhythmic variation in Cyp4x1 and Cyp2c11 gene and protein expression with a 12-h period and parallel rhythmic production of EETs. Our data suggest there is circadian regulation of Cyp4x1 and Cyp2c11 gene expression. Such rhythmic EETs production may contribute to circadian changes in blood flow and alter risk of adverse cardiovascular events throughout the day.
Author List
Carver KA, Lourim D, Tryba AK, Harder DRAuthor
David Harder PhD, MS Emeritus Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ARNTL Transcription FactorsAnimals
Aryl Hydrocarbon Hydroxylases
Astrocytes
Brain
Cells, Cultured
Circadian Rhythm
Conserved Sequence
Cytochrome P-450 Enzyme System
Cytochrome P450 Family 2
Endothelial Cells
Gene Expression Regulation, Enzymologic
Male
Promoter Regions, Genetic
Rats
Rats, Sprague-Dawley
Rats, Wistar
Steroid 16-alpha-Hydroxylase
