AMPK/NF-κB通路失衡在孕期炎症刺激致子代大鼠高血压中的作用及机制研究

Under the successive supports from National Scientific Foundation Council, our institution raised and verified a new conception that hypertension origins from prenatal inflammatory stimulation. Based on this conception, we find that offspring from prenatal inflammation exposure have increased sensitivity of blood pressure to DOCA-salt challenge, while antioxidant could prevent blood pressure elevation and vascular damage. These results suggest that oxidative stress is involved in offspring’ hypertension but the exact mechanism is unclear..Combination with the preliminary results that the gene expression levels of mitochondrial fusion and fission decreased in offspring from prenatal inflammation exposure after a second risk factor exposure, we suppose that mitochondrial fusion and fission disorder might be the main reason for offspring’s hypertension. The project will focus on the clue of mitochondrial fusion and fission disorder, exploring its mechanisms from the points of AMPK/NF-κB imbalance and its relationship with prenatal inflammation-induced offspring’ hypertension, which will provide new ideas and deepen the understanding of the pathogenesis of essential hypertension and provide the experimental basis to find a new strategy of intervention.

本课题组在NSFC连续资助下提出并证实了“高血压发生要追溯来自于孕期炎症”的新观点。预实验发现孕期炎症刺激子代动物给予醋酸脱氧皮质酮联合高盐饮水（DOCA-salt）再次刺激后血压敏感性增加，抗氧化剂可以明显改善DOCA-salt引起的血压升高及血管损伤，提示氧化应激参与了子代高血压的发生，但具体的机制仍不清楚。结合预实验发现受到再次刺激时孕期炎症刺激子代动物线粒体融合分裂明显降低，推测线粒体融合分裂异常导致的氧化应激可能是子代动物发生高血压的重要原因之一。本项目即以线粒体融合分裂异常为切入点，从AMPK/NF-κB失衡的角度研究其产生机制以及与子代高血压的关系，旨在为深化原发性高血压发病机制的认识提供新思路,并为寻找干预新策略提供实验依据。

在前期发现孕期炎症刺激后子代高血压大鼠DOCA-salt再刺激时的血压显著升高，血管壁明显增厚，血管损伤程度明显加重的基础上，本项目以线粒体融合分裂异常为切入点，研究孕期炎症刺激后子代高血压大鼠线粒体融合及其在孕期刺激子代高血压大鼠血管局部的变化规律。我们研究结果发现孕期炎症刺激导致子代大鼠再受到DOCA-salt刺激时AMPK信号通路明显降低，同时NF-κB则显著激活，导致PGC-1α不能像正常大鼠那样快速恢复到正常水平导致PGC-1α一直处于低水平状态，进而影响了UCP2蛋白水平的表达以及线粒体融合分裂相关基因的表达水平，导致线粒体融合分裂降低，产生氧化应激，加重高子代血压的发展。 通过本课题，初步阐明了孕期炎症刺激子代大鼠血管线粒体融合分裂基因变化的特点、规律、分子基础及其与子代高血压发生的关系，并探讨了AMPK和NF-κB通路的失衡在孕期炎症暴露子代大鼠高血压发生发展中的作用。通过上述研究，为深化原发性高血压（EH）发病机制提供新的思路和较丰富的基础素材，同时为寻找原发性高血压新的有效防治靶点提供有益线索。 在该课题资助下，发表SCI论文3篇（SCI收录刊物Frontiers in immunology，影响因子5.08，Acta Pharmacologica Sinica，影响因子5.06和American Journal of Cancer Research, 影响因子5.17）。协助培养博士研究生2名，课题负责人获聘中国药理学会抗炎免疫药理学专业委员会青年委员，获得湖南省自然科学基金青年项目1项。