Fiedler Jan, Breckwoldt Kaja, Remmele Christian W, Hartmann Dorothee, Dittrich Marcus, Pfanne Angelika, Just Annette, Xiao Ke, Kunz Meik, Müller Tobias, Hansen Arne, Geffers Robert, Dandekar Thomas, Eschenhagen Thomas, Thum Thomas
Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany; Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.
Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg, Eppendorf, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany.
J Am Coll Cardiol. 2015 Nov 3;66(18):2005-2015. doi: 10.1016/j.jacc.2015.07.081.
Long noncoding ribonucleic acids (lncRNAs) are a subclass of regulatory noncoding ribonucleic acids for which expression and function in human endothelial cells and angiogenic processes is not well studied.
The authors discovered hypoxia-sensitive human lncRNAs via next-generation ribonucleic acid sequencing and microarray approaches. To address their functional importance in angiogenic processes, several endothelial lncRNAs were characterized for their angiogenic characteristics in vitro and ex vivo.
Ribonucleic acid sequencing and microarray-derived data showed specific endothelial lncRNA expression changes after hypoxia. Validation experiments confirmed strong hypoxia-dependent activation of 2 intergenic lncRNAs: LINC00323 and MIR503HG.
Silencing of these lncRNA transcripts led to angiogenic defects, including repression of growth factor signaling and/or the key endothelial transcription factor GATA2. Endothelial loss of these hypoxia-driven lncRNAs impaired cell-cycle control and inhibited capillary formation. The potential clinical importance of these endothelial lncRNAs to vascular structural integrity was demonstrated in an ex vivo model of human induced pluripotent stem cell-based engineered heart tissue.
The authors report an expression atlas of human hypoxia-sensitive lncRNAs and identified 2 lncRNAs with important functions to sustain endothelial cell biology. LncRNAs hold great promise to serve as important future therapeutic targets of cardiovascular disease.
长链非编码核糖核酸（lncRNAs）是一类调控性非编码核糖核酸，其在人内皮细胞及血管生成过程中的表达和功能尚未得到充分研究。
作者通过下一代核糖核酸测序和微阵列方法发现了对缺氧敏感的人lncRNAs。为了阐明它们在血管生成过程中的功能重要性，对几种内皮lncRNAs的体外和离体血管生成特性进行了表征。
核糖核酸测序和微阵列衍生数据显示缺氧后内皮lncRNA表达有特定变化。验证实验证实了2种基因间lncRNAs（LINC00323和MIR503HG）强烈的缺氧依赖性激活。
这些lncRNA转录本的沉默导致血管生成缺陷，包括生长因子信号传导和/或关键内皮转录因子GATA2的抑制。这些由缺氧驱动的lncRNAs在内皮细胞中的缺失损害了细胞周期控制并抑制了毛细血管形成。在基于人诱导多能干细胞的工程心脏组织的离体模型中证明了这些内皮lncRNAs对血管结构完整性的潜在临床重要性。
作者报告了人缺氧敏感lncRNAs的表达图谱，并鉴定了2种对维持内皮细胞生物学具有重要功能的lncRNAs。lncRNAs有望成为未来心血管疾病的重要治疗靶点。
