自噬
昼夜节律
细胞凋亡
生物钟
基因沉默
细胞生物学
血管平滑肌
生物
内科学
时钟
内分泌学
程序性细胞死亡
PI3K/AKT/mTOR通路
ATG5型
细胞生长
信号转导
化学
细胞
生物化学
基因
医学
平滑肌
作者
Zhenyu Guo,Baixue Yu,Xu Li,Xiaohu Yang,Chen Wang,Longhua Fan
标识
DOI:10.1007/s10735-021-10000-6
摘要
Defective autophagy in vascular smooth muscle cells (VSMCs) in response to oxidative stress can lead to cellular apoptosis and plaque instability. Previous studies have revealed that the circadian clock system is involved in autophagic regulation and plaque progression. However, the mechanism by which circadian rhythmicity influences VSMC autophagy and plaque stability remains unclear. Our study described the circadian profiles in atheromatous plaques and verified the role of circadian misalignment in VSMC autophagy and apoptosis. We found that the mRNA expression levels of circadian locomotor output cycles protein kaput (CLOCK) and Beclin 1 were significantly decreased in unstable plaques compared with stable plaques. No significant differences were observed in other circadian rhythm genes. VSMCs treated with oxidized low-density lipoprotein (ox-LDL, 80 μg/ml) exhibited abnormal circadian rhythmicity and impaired autophagy, as evidenced by consistent decreases in CLOCK and Beclin 1 expression, suggesting a correlation between CLOCK and autophagy. CLOCK protein expression was inhibited by ox-LDL, accompanied by defective autophagy and an increased apoptosis rates (P < 0.05). Administration of rapamycin (10 nM) reversed the effect of ox-LDL on VSMC autophagy and apoptosis. Finally, CLOCK silencing led to a considerable decrease in autophagy. VSMCs with stable CLOCK silencing also showed an increased apoptosis rate. In addition, gene silencing of CLOCK in VSMCs counteracted the effects of moderate rapamycin concentrations on autophagy and apoptosis. In conclusion, these findings suggested that the CLOCK-dependent rapamycin signaling pathway is a critical mediator in ox-LDL-induced VSMCs with defective autophagy that exacerbates plaque destabilization.
科研通智能强力驱动
Strongly Powered by AbleSci AI