Department of Neurology, Shanghai Fifth People(')s Hospital of Fudan University, Shanghai, China.
Human Phenome Institute of Fudan University, Shanghai, China.
Cell Signal. 2023 Oct;110:110834. doi: 10.1016/j.cellsig.2023.110834. Epub 2023 Jul 31.
FBN1 mutation promotes the degeneration of microfibril structures and extracellular matrix (ECM) integrity in the tunica media of the aorta in Marfan syndrome. However, whether FBN1 modulates cervical artery dissection (CAD) development and the potential molecular mechanisms of abnormal FBN1 in CAD remains elusive. In this study, FBN1 deficiency participated in the development of CAD and influenced the proliferation, apoptosis, and migration of vascular smooth muscle cells. FBN1 knockout induced alternations in mRNA levels of the transcriptome, protein expression of the proteome, and abundance of N-glycosylation of the N-glycoproteome. Comprehensive analysis of multiple omics showed up-regulation in mRNA levels of ECM proteins; yet, both the ECM protein levels and relative abundance of N-glycosylation were decreased. Moreover, we performed in vivo experiments to confirm the altered glycosylation of proteins in vascular smooth muscle cells. In conclusion, FBN1 deletion in vascular smooth muscle cells can result in altered N-glycosylation of ECM protein, which were critical for the stability of ECM and the process of CAD. This may open the way for a novel therapeutic strategy to treat people with CAD.
FBN1 突变可促进马凡综合征主动脉中层中小纤维结构和细胞外基质（ECM）完整性的退化。然而，FBN1 是否调节颈动脉硬化性夹层（CAD）的发生以及 CAD 中异常 FBN1 的潜在分子机制仍不清楚。在这项研究中，FBN1 缺失参与了 CAD 的发生，并影响了血管平滑肌细胞的增殖、凋亡和迁移。FBN1 敲除诱导了转录组 mRNA 水平、蛋白质组蛋白表达和 N-糖蛋白组 N-糖基化丰度的改变。对多个组学的综合分析显示，ECM 蛋白的 mRNA 水平上调；然而，ECM 蛋白水平和相对 N-糖基化丰度均降低。此外，我们进行了体内实验来证实血管平滑肌细胞中蛋白质糖基化的改变。总之，血管平滑肌细胞中 FBN1 的缺失可导致 ECM 蛋白的 N-糖基化改变，这对 ECM 的稳定性和 CAD 的发生过程至关重要。这可能为治疗 CAD 患者开辟了新的治疗策略。
