Lai Chih-Hung, Chen Aleysha T, Burns Andrew B, Sriram Kiran, Luo Yingjun, Tang Xiaofang, Branciamore Sergio, O'Meally Denis, Chang Szu-Ling, Huang Po-Hsun, Shyy John Y-J, Chien Shu, Rockne Russell C, Chen Zhen Bouman
Department of Diabetes Complications and Metabolism, City of Hope, Duarte, CA, United States.
Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan.
Front Cell Dev Biol. 2021 Feb 12;9:635307. doi: 10.3389/fcell.2021.635307. eCollection 2021.
The homeostasis of vascular endothelium is crucial for cardiovascular health and endothelial cell (EC) aging and dysfunction could negatively impact vascular function. Leveraging transcriptome profiles from ECs subjected to various stimuli, including time-series data obtained from ECs under physiological pulsatile flow vs. pathophysiological oscillatory flow, we performed principal component analysis (PCA) to identify key genes contributing to divergent transcriptional states of ECs. Through bioinformatics analysis, we identified that a long non-coding RNA (lncRNA) RAMP2-AS1 encoded on the antisense of RAMP2, a determinant of endothelial homeostasis and vascular integrity, is a novel regulator essential for EC homeostasis and function. Knockdown of RAMP2-AS1 suppressed RAMP2 expression and caused EC functional changes promoting aging, including impaired angiogenesis and increased senescence. Our study demonstrates an integrative approach to quantifying EC aging based on transcriptome changes, which also identified a number of novel regulators, including protein-coding genes and many lncRNAs involved EC functional modulation, exemplified by RAMP2-AS1.
血管内皮的稳态对于心血管健康至关重要，而内皮细胞（EC）衰老和功能障碍会对血管功能产生负面影响。利用受到各种刺激的内皮细胞的转录组图谱，包括从生理脉动流与病理生理振荡流条件下的内皮细胞获得的时间序列数据，我们进行了主成分分析（PCA）以确定导致内皮细胞不同转录状态的关键基因。通过生物信息学分析，我们发现一种在内皮稳态和血管完整性的决定因素RAMP2的反义链上编码的长链非编码RNA（lncRNA）RAMP2-AS1是内皮细胞稳态和功能所必需的新型调节因子。敲低RAMP2-AS1会抑制RAMP2表达，并导致促进衰老的内皮细胞功能变化，包括血管生成受损和衰老增加。我们的研究展示了一种基于转录组变化来量化内皮细胞衰老的综合方法，该方法还鉴定出了许多新型调节因子，包括蛋白质编码基因和许多参与内皮细胞功能调节的lncRNA，以RAMP2-AS1为例。
