Department of Pharmacology & Toxicology, Georgia Regents University, Augusta, Georgia, United States of America.
PLoS One. 2013 Oct 25;8(10):e78626. doi: 10.1371/journal.pone.0078626. eCollection 2013.
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.
最近的研究表明，生物钟紊乱与动脉结构和血管僵硬的病理性重塑有关。此外，慢性生物钟紊乱与内皮细胞反应和信号转导功能障碍有关。活性氧已成为血管病理学的关键调节因子。此前，我们已经证明生物钟功能障碍通过 eNOS 解偶联加剧超氧化物的产生。迄今为止，生物钟突变对血管 NADPH 氧化酶表达和功能的影响尚不清楚。本研究的目的是确定生物钟是否控制动脉中 Nox4 的表达和过氧化氢的形成，特别是在内皮细胞和血管平滑肌细胞中。在生物钟功能失调（Bmal1-KO 小鼠）的小鼠的主动脉中，过氧化氢和 Nox4 的表达增加。此外，核心生物钟转录因子激活 Nox4 基因启动子。最后，在同步培养的人内皮细胞中，Nox4 基因表达表现出节律性振荡。这些数据表明，生物钟在控制 Nox4 中起重要作用，生物钟的破坏会导致随后产生反应性氧物质。
