高血脂通过抑制Smarcd1损害血管平滑肌细胞生物时钟和生理稳态的分子机制研究

Many physiological events in mammals, including locomotor activity, sleep, blood pressure, circulating hormones and energy metabolism show diurnal fluctuation. Recent studies indicate that clock genes intensively regulate the function of cardiovascular system. However, the molecular mechanism linking circadian clock and the homeostasis of cardiovascular system remains unknown. Our preliminary data show that Smarcd1, a member of SWI/SNF chromatin remodeling complex family, is rhythmically expressed in vascular smooth muscle cells (VSMCs). Stimulation by free fatty acids (FFAs) significantly reduces the amplititude of clock gene oscillation, as well as inhibiting Smarcd1 expression. In contrast, adenovirus-mediated Smarcd1 overexpression partially reverses the suppressive effects of FFAs on clock genes. In the current project, we will further investigate the molecular mechanism through which hyperlipidemia regulates Smarcd1 and affacts the circadian clock and physiological function (e.g. proliferation and migration) of VSMCs.

哺乳动物的许多生理活动具有昼夜节律性，比如睡眠、血压、血液激素水平以及能量代谢都显示出以24小时为周期的波动性。近年来研究表明，时钟基因深度参与调控心血管系统的功能。然而，生物时钟和心血管系统稳态之间的分子联系机制尚未明了。我们的预实验结果显示，SWI/SNF染色体重塑复合物家族成员Smarcd1在血管平滑肌细胞（VSMCs）中呈现表达的振荡性。用脂肪酸刺激VSMCs，能够显著降低时钟基因振荡的振幅，并抑制Smarcd1的表达。而腺病毒介导的Smarcd1过表达部分逆转了脂肪酸对时钟基因的遏制效应。在本项目中，我们将进一步探讨高血脂通过调控Smarcd1影响VSMCs生物时钟和生理功能（增殖与迁移）的分子机制。本项目的研究将丰富现有的生物时钟和细胞生理功能协同整合的理论，并且为从生物时钟的角度治疗心血管疾病提供理论依据。

哺乳动物的许多生理活动具有昼夜节律性，比如睡眠、血压、血液激素水平以及能量代谢都显示出以24小时为周期的波动性。近年来研究表明，时钟基因深度参与调控心血管系统的功能。然而，生物时钟和心血管系统稳态之间的分子联系机制尚未明了。我们的研究发现Smarcd1在大鼠VSMCs中呈现出振荡性表达，其表达振幅被体内高脂饮食信号以及体外游离脂肪酸刺激所抑制。分子水平实验证实，Smarcd1与RORα结合，协同激活bmal1启动子的转录活性，且二者的结合由PGC-1α所介导。在VSMCs的生理功能方面，我们发现过表达Smarcd1，能够显著抑制FFAs所诱导的VSMCs增殖、迁移及黏附，同时抑制Erk/MAPK以及Akt磷酸化水平。并且，Smarcd1的这些效应会被Bmal1的敲降所减弱。综上所述，Smarcd1在协同调节VSMCs的生物时钟和生理功能稳态方面扮演着重要的角色。