Abstract
Objectives and design:
As a pleiotropic inflammatory cytokine, TNF-α could act as a kind of zeitgeber mediator to integrate with circadian clock and modulate inflammatory signaling. We aimed to investigate how circadian gene Bmal1 regulating inflammation in vascular smooth muscle cells (VSMCs) upon TNF-α stimulation.
Methods
Circadian rhythmicity of Bmal1 expression was detected in the mouse VSMCs challenged with TNF-α, and then Bmal1 was knocked down or overexpressed by adenovirus transfection to investigate the effects and machines of Bmal1 on inflammatory signaling.
Results
1) TNF-α stimulated Bmal1 transcription and disrupted its circadian expression in VSMCs. 2) Transcriptional activation of Bmal1 furtherly activated TNF-α-induced- NF-κB signaling and exacerbated VSMCs inflammation by triggering oxidative stress. 3) TNF-α-activated JNK signaling enhanced REV-ERBα phosphorylation and degradation, and thus promoted Bmal1 transcription in VSMCs.
Conclusion
Our work identified a specific pathway by which the transcriptional activation of Bmal1, mediated by the TNF-α-induced REV-ERBα phosphorylation, triggered oxidative stress to exacerbate inflammatory response in VSMCs, which represents a new opportunity for clock gene Bmal1 being a potential diagnostic marker and therapeutic target for TNF-α mediated vascular inflammation.