CerS6调控C16:0参与血压和血管功能调节的机制研究

高血压是威胁心血管健康的主要因素，其发生机制至今仍不清楚。我们前期研究提示，鞘磷脂通路的核心物质神经酰胺 (d18:1/16:0)（简称C16:0）与人群高血压患病显著相关。C16:0是由神经酰胺合酶6（CerS6）产生，我们发现在高血压模型鼠的肾脏中CerS6转录和表达水平显著低于正常对照组。我们推测CerS6/C16:0可能是参与血压和血管功能调节的关键分子。本研究拟 1）利用已建立的人群队列，分析CerS6基因多态性和C16:0血清水平与高血压、血管损伤及变化、及心血管事件的关系；2）明确过表达或敲除CerS6基因对血管紧张素II诱导高血压模型鼠血压和血管舒缩的作用；检测血管及细胞FGF21、线粒体功能、炎症因子等变化，探讨CerS6发挥作用的上下游通路；3）探讨CerS6是否参与CerS非特异性抑制剂FTY720对血管和血压的调节作用。研究有助于揭示高血压发病新机制及治疗新靶点。

Hypertension is a major threat to cardiovascular health in the world, but its mechanism is still unclear. Our previous results in population studies suggest that the sphingomyelin pathway, particularly its core substance ceramide (d18:1/16:0) (C16:0), was significantly associated with hypertension prevalence. C16:0 is mainly produced by the upstream ceramide synthetase 6 (CerS6). We found that the transcription and expression levels of CerS6 in hypertensive mouse models were significantly lower than those in the normotensive control group. We therefore hypothesize that CerS6-regulated C16:0 might be a key molecule involved in vascular dysfunction and hypertension. We intend to explore: 1) the association of CerS6 genetic polymorphisms and serum C16:0 level with hypertension, vascular injury and cardiovascular events in our established population cohorts; 2) the role of CerS6 in angiotensin II-induced hypertensive mouse models overexpressing or being knocked-out the CerS6 gene, and the upstream and downstream pathways of CerS6 by detecting the changes of FGF21, mitochondrial function and inflammation factors in arteries and vascular cells; 3) if CerS6 was involved in the regulation of blood pressure and vascular function by an non-specific CerS inhibitor, FTY720. The study will help to reveal new mechanisms of hypertension and new target for the treatment of hypertension.