在慢性间歇性低氧环境下暴露的大鼠主动脉中血管紧张素 II 型 1 型受体的表达：p38MAPK 和 ERK1/2 信号通路的影响。

Ang II type 1 receptor expression in rat aorta exposed to chronic intermittent hypoxia: effects of p38MAPK and ERK1/2 signaling.

机构信息

Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.

出版信息

Chin Med J (Engl). 2013;126(17):3264-9.

PMID:24033947

Abstract

BACKGROUND

Obstructive sleep apnea is a frequent medical condition consisting of repetitive sleep-related episodes of upper air ways obstruction and can lead to hypertension. Ang II type 1 receptor (AT1R) played important roles in hypertension since it binds with Ang II, controlling salt-water and blood pressure homeostasis. This study explores rat aorta AT1R expression during intermittent hypoxia (IH) and the signaling pathways involved.

METHODS

A rat model and a cell model used a BioSpherix-OxyCycler A84 system and a ProOx C21 system respectively. The arterial blood pressure was recorded by a Nihon Kohden Polygraph System. Immunohistochemic was used to focus and analyze the expression of AT1R in rat aorta. Real-time PCR and Western blotting were used to explore the signaling pathways that participated in AT1R expression.

RESULTS

In this study, we found that chronic intermittent hypoxia (CIH) induced AT1R transcription which increased the blood pressure in rat aorta compared to normoxia and to sustained hypoxia. The AT1R protein expression in the aorta was similar to the real-time PCR results. We explored the signaling mechanisms involved in the AT1R induction in both rat aorta and the aortic endothelial cells by real-time PCR and Western blotting. Compared to normoxia, CIH increased ERK1 mRNA transcription but not ERK2 or p38MAPK in the aorta; whereas sustained hypoxia (SH) upregulated ERK2 but not ERK1 or p38MAPK mRNA. In cells, IH induced AT1R expression with ERK1/2 phosphorylation but reduced p38MAPKs phosphorylation, whereas SH induced only ERK1/2 phosphorylation. The ERK1/2 inhibitor PD98059 attenuated the IHinduced AT1R increase but the p38MAPK inhibitor SB203580 did not.

CONCLUSIONS

Our results indicate that CIH induced the elevation of rat blood pressure and aorta AT1R expression. Moreover, AT1R expression in IH and sustained hypoxia might be regulated by different signal transduction pathways, highlighting a novel regulatory function through ERK1/2 signaling in IH.

摘要

背景

阻塞性睡眠呼吸暂停是一种常见的医学病症，由睡眠相关的上呼吸道阻塞反复发作引起，可导致高血压。血管紧张素 II 型 1 型受体（AT1R）与血管紧张素 II 结合，控制盐和水以及血压稳态，在高血压中发挥着重要作用。本研究探讨了间歇性低氧（IH）期间大鼠主动脉 AT1R 的表达及其相关信号通路。

方法

使用 BioSpherix-OxyCycler A84 系统和 ProOx C21 系统分别建立大鼠模型和细胞模型。使用 Nihon Kohden Polygraph 系统记录动脉血压。免疫组化聚焦和分析大鼠主动脉 AT1R 的表达。实时 PCR 和 Western blot 用于探索参与 AT1R 表达的信号通路。

结果

本研究发现，慢性间歇性低氧（CIH）诱导 AT1R 转录，与常氧和持续低氧相比，大鼠主动脉的血压升高。主动脉中 AT1R 蛋白表达与实时 PCR 结果相似。我们通过实时 PCR 和 Western blot 探讨了常氧和持续低氧中 AT1R 诱导的信号机制。与常氧相比，CIH 增加了主动脉中 ERK1 mRNA 的转录，但不增加 ERK2 或 p38MAPK；而持续低氧（SH）则上调了 ERK2，但不增加 ERK1 或 p38MAPK mRNA。在细胞中，IH 诱导 AT1R 表达并使 ERK1/2 磷酸化，但降低 p38MAPKs 磷酸化，而 SH 仅诱导 ERK1/2 磷酸化。ERK1/2 抑制剂 PD98059 减弱了 IH 诱导的 AT1R 增加，但 p38MAPK 抑制剂 SB203580 则没有。