Prenatal inflammation-induced NF-κB dyshomeostasis contributes to renin-angiotensin system over-activity resulting in prenatally programmed hypertension in offspring.
Prenatal inflammation-induced NF-κB dyshomeostasis contributes to renin-angiotensin system over-activity resulting in prenatally programmed hypertension in offspring.
复制标题
产前炎症诱导的 NF-κB 稳态失衡导致肾素-血管紧张素系统过度活跃，导致后代出现产前程序性高血压
DOI：
10.1038/srep21692
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发表时间：
2016-02-15
影响因子：
4.6
通讯作者：
Li X
中科院分区：
文献类型：
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作者：
Deng Y;Deng Y;He X;Chu J;Zhou J;Zhang Q;Guo W;Huang P;Guan X;Tang Y;Wei Y;Zhao S;Zhang X;Wei C;Namaka M;Yi P;Yu J;Li X
涉及使用产前计划高血压的研究已显示可能有助于预防原发性高血压（EH）。我们之前的研究表明，在脂多糖（LPS）刺激下，妊娠期Sprague-Dawley大鼠的产前炎症刺激导致后代主动脉功能障碍和高血压。本研究发现，产前LPS暴露导致从胎儿到成人的NF-κB失衡，其特征是PI3K-Akt激活介导i -κ α蛋白降解，NF-κB自负反馈回路受损介导胸主动脉i -κ α mRNA新合成减少（妊娠第20天，出生后第7周和第16周）。产前或产后暴露于i -κB α降解抑制剂鹿蹄草碱二硫代氨基甲酸酯可有效阻断胸主动脉NF-κB活化、内皮功能障碍和肾素-血管紧张素系统（RAS）过度活跃，导致产前暴露于LPS的后代血压降低。令人惊讶的是，NF-κB失衡和RAS过度活跃仅在胸主动脉中发现，而在肠系膜上动脉中没有发现。总之，我们的数据表明，产前炎症暴露引起的早期生命NF-κB失衡通过触发RAS过度活性在EH的发展中起重要作用。我们得出结论，生命早期NF-κB失衡是EH的关键预测因子，因此抑制NF-κB是预防EH的有效干预策略。
Studies involving the use of prenatally programmed hypertension have been shown to potentially contribute to prevention of essential hypertension (EH). Our previous research has demonstrated that prenatal inflammatory stimulation leads to offspring’s aortic dysfunction and hypertension in pregnant Sprague-Dawley rats challenged with lipopolysaccharide (LPS). The present study found that prenatal LPS exposure led to NF-κB dyshomeostasis from fetus to adult, which was characterized by PI3K-Akt activation mediated degradation of IκBα protein and impaired NF-κB self-negative feedback loop mediated less newly synthesis of IκBα mRNA in thoracic aortas (gestational day 20, postnatal week 7 and 16). Prenatal or postnatal exposure of the IκBα degradation inhibitor, pyrollidine dithiocarbamate, effectively blocked NF-κB activation, endothelium dysfunction, and renin-angiotensin system (RAS) over-activity in thoracic aortas, resulting in reduced blood pressure in offspring that received prenatal exposure to LPS. Surprisingly, NF-κB dyshomeostasis and RAS over-activity were only found in thoracic aortas but not in superior mesenteric arteries. Collectively, our data demonstrate that the early life NF-κB dyshomeostasis induced by prenatal inflammatory exposure plays an essential role in the development of EH through triggering RAS over-activity. We conclude that early life NF-κB dyshomeostasis is a key predictor of EH, and thus, NF-κB inhibition represents an effective interventional strategy for EH prevention.