Abstract：
Coronary artery calcification (CAC) is a hallmark event in the pathogenesis of cardiovascular disease, involving the phenotypic transformation of vascular smooth muscle cells (VSMC) towards an osteogenic state. Despite this understanding, the molecular mechanisms governing the VSMC osteogenic switch remain incompletely elucidated. Here, we sought to examine the potential role of circular RNA (circRNA) in the context of CAC. Through transcriptome analysis of circRNA-seq, we identified circTOP1 as a potential candidate circRNA in individuals with CAC. Furthermore, we observed that overexpression of circTOP1 exacerbated vascular calcification in a CAC model. Subsequent pull-down assays revealed an interaction between circTOP1 and PTBP1, a putative target gene of circTOP1 in the context of CAC. In both in vivo and in vitro experiments, we observed heightened expression of circTOP1 and PTBP1 in the CAC model, and noted that reducing circTOP1 expression effectively reduced calcium salt deposits and mineralized nodules in model mice. Additionally, in vitro experiments demonstrated that overexpression of PTBP1 reversed the weakening of signaling caused by silencing circTOP1, thereby exacerbating the osteogenic transition and calcification of VSMC. Collectively, our findings suggested that circTOP1 promotes CAC by modulating PTBP1 expression to mediate VSMC transdifferentiation.
摘要：
冠状动脉钙化(CAC)是心血管疾病发病的标志性事件,涉及血管平滑肌细胞（VSMC）向成骨状态的表型转化。尽管有这样的理解,控制VSMC成骨开关的分子机制仍未完全阐明。这里,我们试图研究环状RNA(circularRNA,circRNA)在CAC中的潜在作用.通过circRNA-seq的转录组分析，我们确定circTOP1为CAC患者的潜在候选circRNA。此外，在CAC模型中,我们观察到circTOP1的过度表达加剧了血管钙化.随后的下拉测定揭示了circTOP1和PTBP1之间的相互作用，PTBP1是CAC背景下circTOP1的推定靶基因。在体内和体外实验中，我们观察到CAC模型中circTOP1和PTBP1的表达增强，并指出减少circTOP1表达可有效减少模型小鼠的钙盐沉积和矿化结节。此外,体外实验表明，PTBP1的过表达逆转了沉默circTOP1引起的信号传导减弱，从而加剧了VSMC的成骨转化和钙化。总的来说，我们的研究结果表明，circTOP1通过调节PTBP1的表达来介导VSMC转分化，从而促进CAC。
