GRK4在孕期不良刺激致子代高血压跨代遗传中的作用和机制研究

Lipopolysaccharide (LPS) exposure in utero results in increased blood pressure in offspring, this phenomenon is not only in the F1 generation, but also can be passed to the next generation. There were dysfunctions of many G coupled protein receptors (GPCRs) with aberrant receptor phosphorylation in F1 rats, accompanied with higher expression of GPCR related kinase 4(GRK4). It is interesting to find that, consistent with the increased blood pressure, the aberrant GPCRs and GRK4 expression also occurred in F2 and F3 rats. Due to the effect of GRK4 on GPCR phosphorylation, it indicated that GRK4 might be the carrier of hypertensive trans-generation. Previous studies showed that LPS increased ROS levels, affected DNMTs, consequently changed gene methylation. Our study found that the methylation in GRK4 promoter was lower in SHRs than WKY control rats, further indicating the lower methylation levels might be the vital carrier of hypertensive trans-generation. Besides of LPS exposure, we also found other adverse factors in pregnancy lead to hypertension in offspring, companied with increased GRK4 expression, suggesting that GRK4 may play an important role in offspring hypertension induced by multiple pregnancy irritation. Therefore, we presume that higher GRK4 expression is the carrier leading to hypertension in offspring of dam with adverse factor exposure during pregnancy. Irritation factors in pregnancy influence DNMTs by ROS, leading to GRK4 methylation is the mechanism. This study will provide new view to uncover the mechanism of hypertension.

孕期脂多糖(LPS)刺激致子代高血压，该现象不仅在子F1代，并且具有连续传代现象。F1代有多个GPCR受体磷酸化和功能改变，伴有GRK4高表达。有趣的是GPCR和GRK4改变在F2和F3中均出现，由于GRK4是GPCR磷酸化的重要激酶，提示其可能是高血压遗传的物质基础。既往显示孕期LPS致ROS增加、影响DNMTs从而影响基因甲基化改变；高血压大鼠GRK4基因启动子区甲基化程度降低，提示GRK4启动子甲基化程度降低可能是其高表达跨代的重要机制。除LPS外，我们还发现多个其它孕期不良刺激均导致F1代血压增高，伴有GRK4表达增高，提示GRK4可能在多种孕期不良刺激致子代高血压中发挥作用。据此，我们推测：GRK4高表达是孕期不良刺激致子代高血压跨代遗传的物质基础。孕期不良刺激通过ROS影响DNMTs表达和活性，从而致GRK4启动子甲基化是其作用机制；该研究将为探索高血压发病机制提供新的角度。

环境因素在高血压发生发展中发挥重要作用，本研究从外部环境（脂多糖、PM2.5）、内环境（糖尿病）因素出发，研究其对危险因素暴露个体子代血压的影响。发现无论孕期脂多糖(LPS)或糖尿病暴露、父代PM2.5暴露均能导致子代血压升高和尿钠排泄障碍。我们以孕期脂多糖(LPS)暴露为例进行深入研究，发现其高血压跨代遗传至少可以传至子5代（F5）。肾脏Rac1-MR信号通路异常激活是孕期LPS暴露致子代高血压的关键机制；氧化应激所导致的H3K9me2的异常表观遗传修饰是孕期LPS暴露致高血压跨代传递的遗传学机制。用抗氧化剂Tempol干预孕鼠可以明显阻断高血压的跨代遗传。该研究揭示了环境因素在高血压跨代遗传中的作用，为表观遗传在高血压中的作用提供了鲜活的例证，并提供了防治高血压传代遗传的靶点。

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