Ephx2基因启动子DNA甲基化异常在高血压血管重塑中的分子机制

The pathogenesis of essential hypertension is very complex, and so far has not been clear. With the deepening of research in epigenetics, DNA methylation is closely related to the pathogenesis of hypertension.We found that compared with normal rats, in spontaneously hypertensive rats Ephx2 gene promoter region significant hypomethylation and mRNA levels and protein are highly expressed by the genome-wide DNA methylation sequencing. Accordingly, we speculate Ephx2 gene DNA methylation involved in hypertensive vascular remodeling process. To further determine whether Ephx2 participents in vascular remodeling and blood pressure regulation or not, this project intends to inject Ephx2-shRNA from tail vein to inhibit the Ephx2 gene expresion of spontaneously hypertensive rats.Then, we observe blood pressure, RAAS system,and vascular inflammatory cytokines,further determine the role of molecular biology of the epoxyeicosatrienoic acids (EET) signaling pathway. It confirmed that the Ephx2 gene methylation correlates with hypertension pathogenesis,and will provide new theoretical basis for the clinical prevention and treatment.

原发性高血压的发病机制非常复杂，迄今为止尚未明确。随着表观遗传学研究的不断深入，DNA甲基化异常与高血压病的发病机制密切相关。通过采用全基因组DNA甲基化测序检测到自发性高血压大鼠动脉血管Ephx2基因启动子区域较正常对照组显著低甲基化，且其mRNA水平和蛋白均高表达。据此，我们推测Ephx2基因的DNA甲基化异常参与了高血压血管重构过程。为进一步确定Ephx2在血管重塑和血压调节中的作用，本项目拟采用Ephx2-shRNA尾静脉注射抑制自发性高血压大鼠的Ephx2基因的表达，观察其对血压、RAAS系统、血管炎症因子等指标的影响，并进一步确定其对于二十碳脂酸（EET）分子生物学信号通路的调控作用，从而证实Ephx2基因甲基化异常与高血压发病机制的相关性，为临床预防与治疗提供新的理论依据。