title: The role of the Nox4-derived ROS-mediated RhoA/Rho kinase pathway in rat hypertension induced by chronic intermittent hypoxia.
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% O2for 60 s and 5% O2for 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Respiratory Disease, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Lu
authors.affiliation: Division of Respiratory Disease, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Kang
authors.affiliation: Division of Respiratory Disease, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China. hukejx@163.com.
authors.forename: Ke
authors.initials: K
authors.lastname: Hu
authors.affiliation: Division of Respiratory Disease, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China.
authors.forename: Si
authors.initials: S
authors.lastname: Tang
authors.affiliation: Division of Respiratory Disease, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China.
authors.forename: Xiufang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Division of Respiratory Disease, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Division of Respiratory Disease, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Respiratory Disease, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Yu
mesh_terms: D000818:Animals; D006973:Hypertension / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D000074663:NADPH Oxidase 4 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D020181:Sleep Apnea, Obstructive / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; C498911:Nox4 protein, rat; D054460:rho-Associated Kinases; C000621224:RhoA protein, rat; D020741:rho GTP-Binding Proteins
keywords: Chronic intermittent hypoxia; Hypertension; NADPH oxidase 4; Obstructive sleep apnea; Oxidative stress; Renal sympathetic nerve activity; RhoA/ROCK pathway