血压相关基因SF3A3在高血压发生和血管重构中的作用和机制

Hypertension is one of the most common chronic diseases in the world, and its pathogenesis remains to be elucidated. We were the first report (Nature Genetics, 2017) that one mRNA splicing factor SF3A3 is a hypertension-associated gene, with the increased expression level of SF3A3 was observed in vascular smooth muscle cells (VSMCs) isolated from individuals with higher hypertension risk. However, little is known about the functional role of SF3A3 in hypertension and cardiovascular disease. Our recent preliminary experiments showed the expression level of SF3A3 were significantly up-regulated in VSMCs and monocyte/macrophages under AngII treatment. Importantly, we also observed the gene expression level of SF3A3 was dramatically elevated in the aorta of AngII-induced hypertensive mice, compared with the control. According to our findings and previous studies, we hypothesized that SF3A3 might promote hypertension through modulating various cell functions, arterial remodelling, stiffness by regulating the downstream genes or related signalling pathways. Therefore, multiple techniques (e.g., RNAi, RNA-seq, LNA, AFM) and various models (e.g., VSMCs, peripheral blood monocytes, Ang II-induced hypertension mice model, as well as patients with hypertension) will be utilized in this study to explore the biological role of SF3A3 in blood pressure control. This study would potentially provide a theoretical basis for the new therapeutic target for hypertension prevention.

高血压是全球最常见的慢性病之一,其发病机制尚不明确。申请人前期研究（Nature Genetics，2017）首次发现mRNA剪接因子SF3A3是高血压相关基因，且高风险人群血管平滑肌细胞（VSMC）该基因表达明显高于低风险人群。然而，迄今国内外无任何报道阐释SF3A3在高血压和心血管疾病方面的作用机制。在预试验中，与对照组相比，SF3A3在AngII处理后的VSMC和单核巨噬细胞的表达上调，且在AngII诱导的高血压小鼠主动脉中该基因的表达也显著升高，进一步提示SF3A3与高血压发生相关。综合分析相关研究报道，我们推测SF3A3可能通调控细胞功能，血管重构，进而参与高血压的发生。我们拟采用RNAi技术、RNA-Seq、LNA在体干预等多项技术，从分子细胞、动物模型、人群层面上研究SF3A3在血压调控中的生物学功能。本项目结果可为高血压防治的新药物靶点提供理论基础。

高血压是全球最常见的慢性病之一, 其发病机制尚不明确。前期研究首次发现mRNA剪接因子SF3A3是高血压相关基因，且高风险人群血管平滑肌细胞（VSMC）该基因表达明显高于低风险人群。然而，迄今国内外无任何报道阐释SF3A3在高血压和心血管疾病方面的作用机制。我们扩大人群样本分析提示SF3A3与高血压明显相关，另外在AngII诱导的高血压小鼠主动脉中SF3A3的表达显著升高；我们体外培养人血管平滑肌细胞及内皮细胞，建立SF3A3低表达细胞模型，发现SF3A3可以参与调控血管平滑肌细胞以及内皮细胞的存活和迁移，内皮细胞毒性及炎症因子表达等，RNA-seq数据分析也提示SF3A3参与调控细胞周期、增殖等信号通路，以上阐明了SF3A3其在高血压调控方面中的生物学功能，为高血压防治的新药物靶点提供理论基础。