Genome-scale analysis of PCSK9 in PC12 cells reveals immune response modulation and alternative splicing of hypoxia response genes

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potential RNA regulatory protein that plays an important role in cholesterol and fatty acid metabolism; however, the genome-wide regulation of gene expression and alternative splicing of PCSK9 remain unclear. Methods: PCSK9 overexpression experiments were performed in rat PC12 cells, and 330 genes were differentially expressed, including 209 upregulated and 121 downregulated genes. Results: The genes regulated by PCSK9 were enriched in immune response-related pathways, which showed enriched CCL2, Cxcl1, and Irf9. Moreover, genes with altered splicing patterns regulated by PCSK9 overexpression were enriched in pathways including the hypoxic response, and the alternative splicing of PKM and ARNT changed significantly. Conclusions: We found that PCSK9 may participate in the progression of ischemic stroke by activating the immune/hypoxia response. Thus, this study extends the functional roles of PCSK9 in ischemic stroke pathogenesis. Significance: PCSK9 involved into the progression of ischemic stroke, which could considered as a therapeutic target for improving ischemic stroke.背景：前蛋白转化酶枯草溶菌素/kexin 9型（Proprotein convertase subtilisin/kexin type 9，PCSK9）是一种潜在的RNA调控蛋白，在胆固醇与脂肪酸代谢过程中发挥关键作用；然而，目前对于PCSK9的全基因组基因表达调控及可变剪接调控机制仍未明确。 方法：在大鼠PC12细胞中开展PCSK9过表达实验，共鉴定出330个差异表达基因，其中上调基因209个、下调基因121个。 结果：受PCSK9调控的基因显著富集于免疫应答相关通路，该通路中CCL2、Cxcl1及Irf9均呈现富集特征。此外，经PCSK9过表达调控、剪接模式发生改变的基因显著富集于缺氧应答等通路，且PKM与ARNT的可变剪接发生显著变化。 结论：本研究发现PCSK9可通过激活免疫/缺氧应答通路参与缺血性脑卒中的病程进展，由此拓展了PCSK9在缺血性脑卒中发病机制中的功能角色。 意义：PCSK9参与缺血性脑卒中的病程进展，可作为改善缺血性脑卒中治疗的潜在靶点。