Circadian clock control of Nox4 and reactive oxygen species in the vasculature

Area of Science:

• Vascular Biology
• Chronobiology
• Molecular Medicine

Background:

• Circadian clock disruption is linked to arterial remodeling, vascular stiffness, and endothelial dysfunction.
• Reactive oxygen species are key regulators in vascular pathology.
• Previous work showed circadian dysfunction exacerbates superoxide via eNOS uncoupling.

Purpose of the Study:

• To determine if the circadian clock controls vascular NADPH oxidase 4 (Nox4) expression and hydrogen peroxide formation in arteries.
• To investigate Nox4 regulation in endothelial and vascular smooth muscle cells.

Main Methods:

• Analysis of Nox4 expression and hydrogen peroxide in aorta of Bmal1-knockout (Bmal1-KO) mice.
• Investigation of Nox4 gene promoter activation by core circadian transcription factors.
• Assessment of Nox4 gene expression rhythms in synchronized human endothelial cells.

Main Results:

• Bmal1-KO mice exhibited increased hydrogen peroxide and Nox4 expression in the aorta.
• Core circadian transcription factors activate the Nox4 gene promoter.
• Nox4 gene expression showed rhythmic oscillations in cultured human endothelial cells.

Conclusions:

• The circadian clock plays a crucial role in regulating vascular Nox4 expression.
• Disruption of the circadian clock leads to increased production of reactive oxygen species, specifically hydrogen peroxide, via Nox4.
• These findings highlight a novel mechanism linking circadian disruption to vascular pathology.