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The role of the Nox4-derived ROS-mediated RhoA/Rho kinase pathway in rat hypertension induced by chronic intermittent hypoxia

  • Sleep Breathing Physiology and Disorders • Original Article
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Abstract

Background

Obstructive sleep apnea syndrome, which is a risk factor for resistant hypertension, is characterized by chronic intermittent hypoxia (CIH) and is associated with many cardiovascular diseases. CIH elicits systemic oxidative stress and sympathetic hyperactivity, which lead to hypertension. Rho kinases (ROCKs) are considered to be major effectors of the small GTPase RhoA and have been extensively studied in the cardiovascular field. Upregulation of the RhoA/ROCK signaling cascade is observed in various cardiovascular disorders, such as atherosclerosis, pulmonary hypertension, and stroke. However, the exact molecular function of RhoA/ROCK in CIH remains unclear and requires further study.

Objective

This study aimed to investigate the role of the NADPH oxidase 4 (Nox4)-induced ROS/RhoA/ROCK pathway in CIH-induced hypertension in rats.

Methods

Male Sprague–Dawley rats were exposed to CIH for 21 days (intermittent hypoxia of 21% O2 for 60 s and 5% O2 for 30 s, cyclically repeated for 8 h/day). We randomly assigned 56 male rats to groups of normoxia (RA) or vertically implemented CIH together with vehicle (CIH-V), GKT137831 (CIH-G), N-acetyl cysteine (NAC) (CIH-N), or Y27632 (CIH-Y). The rats in the RA group were continuously exposed to room air, whereas the rats in the other groups were exposed to CIH. Systolic blood pressure (BP) was monitored at the beginning of each week. After the experiment, renal sympathetic nerve activity (RSNA) was recorded, and serum and renal tissues were subjected to molecular biological and biochemical analyses.

Results

Compared with the BP of RA rats, the BP of CIH-V rats started to increase 2 weeks after the beginning of the experiment, subsequently stabilizing at a high level at the end of the third week. CIH increased both RSNA and oxidative stress. This response was attenuated by treatment of the rats with GKT137831 or NAC. Inhibiting Nox4 activity or ROS production reduced RhoA/ROCK expression. Treatment with Y27632 reduced both BP and RSNA in rats exposed to CIH.

Conclusion

Hypertension can be induced by CIH in SD rats. The CIH-induced elevation of BP is at least partially mediated via the Nox4-induced ROS/RhoA/ROCK pathway.

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Acknowledgements

We thank Dr. Jing Feng and Prof. Baoyuan Chen, Respiratory Department, Tianjin Medical University General Hospital, China, for their support with the intermittent hypoxia chamber and the gas control delivery system used in this study.

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Authors and Affiliations

  1. Division of Respiratory Disease, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China

    Wen Lu, Jing Kang, Ke Hu, Si Tang, Xiufang Zhou, Lifang Xu, Yuanyuan Li & Shuhui Yu

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  1. Wen Lu
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  2. Jing Kang
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  3. Ke Hu
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Correspondence to Ke Hu.

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Funding

The National Natural Science Foundation of China provided financial support in the form of national natural science funding (No.81070065, 81370181). The sponsor had no role in the design or conduct of this research.

Conflict of interest

The authors declare that they have no conflict of interest.

Animal experiments

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

Author contributions

WL and JK: Directly participated in the execution of the study and molecular biology experiment

KH: Study planning, analysis of the study and writing of the manuscript

ST, XZ, LX, YL, and SY: CIH exposure of rats and gas control delivery

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Lu, W., Kang, J., Hu, K. et al. The role of the Nox4-derived ROS-mediated RhoA/Rho kinase pathway in rat hypertension induced by chronic intermittent hypoxia. Sleep Breath 21, 667–677 (2017). https://doi.org/10.1007/s11325-016-1449-2

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