title: Circadian clock control of Nox4 and reactive oxygen species in the vasculature.
abstract: Recent studies have shown that circadian clock disruption is associated with pathological remodeling in the arterial structure and vascular stiffness. Moreover, chronic circadian disruption is associated with dysfunction in endothelial responses and signaling. Reactive oxygen species have emerged as key regulators in vascular pathology. Previously, we have demonstrated that circadian clock dysfunction exacerbates superoxide production through eNOS uncoupling. To date, the impact of circadian clock mutation on vascular NADPH oxidase expression and function is not known. The goal in the current study was to determine if the circadian clock controls vascular Nox4 expression and hydrogen peroxide formation in arteries, particularly in endothelial and vascular smooth muscle cells. In aorta, there was an increase in hydrogen peroxide and Nox4 expression in mice with a dysfunctional circadian rhythm (Bmal1-KO mice). In addition, the Nox4 gene promoter is activated by the core circadian transcription factors. Lastly, in synchronized cultured human endothelial cells, Nox4 gene expression exhibited rhythmic oscillations. These data reveal that the circadian clock plays an important role in the control of Nox4 and disruption of the clock leads to subsequent production of reaction oxygen species.
authors.affiliation: Department of Pharmacology & Toxicology, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Ciprian B
authors.initials: CB
authors.lastname: Anea
authors.forename: Maoxiang
authors.initials: M
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: M Irfan
authors.initials: MI
authors.lastname: Ali
authors.forename: C Michael M
authors.initials: CM
authors.lastname: Hart
authors.forename: David W
authors.initials: DW
authors.lastname: Stepp
authors.forename: Yevgeniy O
authors.initials: YO
authors.lastname: Kovalenkov
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Merloiu
authors.forename: Paramita
authors.initials: P
authors.lastname: Pati
authors.forename: David
authors.initials: D
authors.lastname: Fulton
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Rudic
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000502:physiology; D057906:Circadian Clocks; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D056930:ARNTL Transcription Factors; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C422943:Nox4 protein, mouse