Abstract
Endothelial dysfunction is one of the main pathological changes in Obstructive sleep apnoea (OSA). The Rho kinase (ROCK) pathway is associated with endothelial dysfunction. However, the interaction between ROCK and nuclear factor of activated T cells isoform c3 (NFATc3) in the development of this pathological response under chronic intermittent hypoxia (CIH) is unclear. To simulate the OSA model, we established a moderate CIH rat model by administering the fraction of inspired O2 (FiO2) from 21% to 9%, 20 times/h, 8 h/day for 3 weeks. Fasudil (ROCK inhibitor, 8 mg/kg/d, i.p.) was administrated in the rats exposed to CIH for 3 weeks. Our results demonstrated that CIH caused significantly endothelial dysfunction, accompanying with increased ET-1 level, decreased eNOS expression and NO production, which reduced ACh-induced vascular relaxation responses. Moreover, RhoA/ROCK-2/NFATc3 expressions were up-regulated. Fasudil significantly improved CIH induced endothelial dysfunction. Data suggested that the ROCK activation is necessary for endothelial dysfunction during CIH.
Highlights
Obstructive sleep apnoea (OSA) is a complete or partial airway obstruction, resulting in significant physiological disturbance with multiple clinical influences [1]
RhoA/ROCK/NFATc3 pathway involved in chronic intermittent hypoxia related biochemical indicators, systolic blood pressures and heart rate (Table 1), and there were no obvious histological changes of the aorta in the fasudil group, compared to the control group (Fig 1)
The results showed that relaxation responses induced by ACh in the endothelium-intact chronic intermittent hypoxia (CIH) group decreased significantly compared with the Normoxia group and, fasudil significantly inhibited the decreased ACh-induced relaxation responses of the endothelium-intact CIH group (P < 0.05) (Fig 3A and 3C)
Summary
Obstructive sleep apnoea (OSA) is a complete or partial airway obstruction, resulting in significant physiological disturbance with multiple clinical influences [1]. RhoA/ROCK/NFATc3 pathway involved in chronic intermittent hypoxia significantly correlated with OSA [7]. Activated ROCK was associated with atherosclerosis and arterial hypertension in experimental rat models [13, 14] and clinical patients [15, 16]. Some studies have demonstrated that NFATc3 was related to pulmonary hypertension induced by CIH in mice [19, 20], the mechanism by which RhoA/ROCK/NFATc3 mediates CIH-induced endothelial dysfunction has not been fully clarified. We imitated OSA using a rat model of CIH to investigate the role of ROCK, and detected whether CIH might affect RhoA/ROCK/NFATc3 mediated endothelial dysfunction in aortas. We investigated if fasudil would restore endothelial dysfunction induced by CIH and its mechanisms
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