Abstract
Purpose: To investigate the role of sodium–hydrogen exchanger-1 (NHE-1) and exercise training on intermittent hypoxia-induced cardiac fibrosis in obstructive sleep apnea (OSA), using an animal model mimicking the intermittent hypoxia of OSA.Methods: Eight-week-old male Sprague–Dawley rats were randomly assigned to control (CON), intermittent hypoxia (IH), exercise (EXE), or IH combined with exercise (IHEXE) groups. These groups were randomly assigned to subgroups receiving either a vehicle or the NHE-1 inhibitor cariporide. The EXE and IHEXE rats underwent exercise training on an animal treadmill for 10 weeks (5 days/week, 60 min/day, 24–30 m/min, 2–10% grade). The IH and IHEXE rats were exposed to 14 days of IH (30 s of hypoxia—nadir of 2–6% O2—followed by 45 s of normoxia) for 8 h/day. At the end of 10 weeks, rats were sacrificed and then hearts were removed to determine the myocardial levels of fibrosis index, oxidative stress, antioxidant capacity, and NHE-1 activation.Results: Compared to the CON rats, IH induced higher cardiac fibrosis, lower myocardial catalase, and superoxidative dismutase activities, higher myocardial lipid and protein peroxidation and higher NHE-1 activation (p < 0.05 for each), which were all abolished by cariporide. Compared to the IH rats, lower cardiac fibrosis, higher myocardial antioxidant capacity, lower myocardial lipid, and protein peroxidation and lower NHE-1 activation were found in the IHEXE rats (p < 0.05 for each).Conclusion: IH-induced cardiac fibrosis was associated with NHE-1 hyperactivity. However, exercise training and cariporide exerted an inhibitory effect to prevent myocardial NHE-1 hyperactivity, which contributed to reduced IH-induced cardiac fibrosis. Therefore, NHE-1 plays a critical role in the effect of exercise on IH-induced increased cardiac fibrosis.
Highlights
Intermittent hypoxia (IH) is a significant symptom in patients with obstructive sleep apnea (OSA) and is caused by recurrent upper airway collapse during sleep (Filgueiras-Rama et al, 2013)
The results showed that the cardiac fibrosis index was significantly higher by 45% in the IH-Veh group compared to the CONVeh group (p < 0.05; Figure 3B)
Our study showed that IH-induced increased myocardial oxidative stress, causing now emerging that sodium-hydrogen exchanger-1 (NHE-1) hyperactivation, subsequently contributing to accumulation fibrotic tissue accumulation in heart sections
Summary
Intermittent hypoxia (IH) is a significant symptom in patients with obstructive sleep apnea (OSA) and is caused by recurrent upper airway collapse during sleep (Filgueiras-Rama et al, 2013). IH in OSA is a major factor in left ventricle (LV) remodeling, cardiac hypertrophy, fibrosis and ventricular dysfunction, leading to impaired cardiac contractility, and heart failure. Evidence is emerging that sodium-hydrogen exchanger-1 (NHE-1) contributes to chronic maladaptive myocardial responses to injury, such as post-infarction myocardial remodeling and likely contributes to the development of heart failure (Karmazyn et al, 2008). Sodium-hydrogen exchange is the primary process by which the cardiac cell extrudes protons, under conditions of intracellular acidosis (Karmazyn et al, 2008; Xue et al, 2010; Feger and Starnes, 2013a). During ischemia/reperfusion, dramatically increased levels of reactive oxygen species (ROS) damage the NHE-1 regulatory capacity; this impairs cardiomyocyte acidification with failure to preserve intracellular pH (Li et al, 2007)
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