title: Rhythmic expression of cytochrome P450 epoxygenases CYP4x1 and CYP2c11 in the rat brain and vasculature.
abstract: 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.
authors: Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors: Koryn A
authors: KA
authors: Carver
authors: Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors: David
authors: D
authors: Lourim
authors: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin.
authors: Andrew K
authors: AK
authors: Tryba
authors: Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin dharder@mcw.edu.
authors: David R
authors: DR
authors: Harder
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology; D001921:Brain / Q000098:blood supply / Q000201:enzymology*; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000502:physiology*; D017124:Conserved Sequence; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D042783:Endothelial Cells / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D008297:Male; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*
chemical_list: D056930:ARNTL Transcription Factors; D003577:Cytochrome P-450 Enzyme System; C465625:cytochrome P-450 4X1; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase
keywords: astrocyte; circadian; epoxyeicosatrienoic acid; epoxygenase