Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, People's Republic of China.
J Pathol. 2014 Jun;233(2):159-69. doi: 10.1002/path.4338. Epub 2014 Mar 28.
Many mammalian physiological processes show diurnal oscillation and are controlled by a circadian clock. Disruption of the circadian clock has been implicated in the pathogenesis of cardiovascular disorders, but the mechanism through which clock and vessel function are integrated is unclear. Here we show that the rhythmicity of key clock genes and Smarcd1, a member of the SWI/SNF chromatin remodelling complex family, is suppressed in the layer of vascular smooth muscle cells (VSMCs) of the thoracic aorta of hyperlipidaemic rats fed a high-fat diet (HFD). Smarcd1 stimulates the transcription of clock genes, notably bmal1, through co-activation of the nuclear orphan receptor RORα in VSMCs. The co-activation of Smarcd1 and RORα is dependent on the mediation of PGC-1α, a transcriptional co-activator. Pathophysiologically, Smarcd1 inhibits VSMC proliferation and migration by blocking cell cycle re-entry and via the activation of kinase signalling pathways. Our results demonstrate that Smarcd1 is a critical node integrating the circadian clock and VSMC physiological homeostasis.
许多哺乳动物的生理过程表现出昼夜节律性，并受生物钟的控制。生物钟的紊乱与心血管疾病的发病机制有关，但时钟和血管功能整合的机制尚不清楚。在这里，我们发现高脂饮食喂养的高脂血症大鼠胸主动脉血管平滑肌细胞（VSMCs）层中关键时钟基因和 SWI/SNF 染色质重塑复合物家族成员 Smarcd1 的节律性受到抑制。Smarcd1 通过在 VSMCs 中共同激活核孤儿受体 RORα 来刺激时钟基因的转录，特别是 bmal1。Smarcd1 和 RORα 的共同激活依赖于 PGC-1α 的介导，PGC-1α 是一种转录共激活因子。在病理生理学上，Smarcd1 通过阻止细胞周期再进入和激活激酶信号通路来抑制 VSMC 的增殖和迁移。我们的研究结果表明，Smarcd1 是整合生物钟和 VSMC 生理稳态的关键节点。
