Abstract
Chronic hypoxia induces pulmonary hypertension and vascular remodeling, which are clinically relevant to patients with chronic obstructive pulmonary disease (COPD) associated with a decreased level of nitric oxide (NO). Oxidative stress and inflammation play important roles in the pathophysiological processes in COPD. We examined the hypothesis that daily administration of melatonin (10 mg/kg) mitigates the pulmonary hypertension and vascular remodeling in chronically hypoxic rats. The right ventricular systolic pressure (RVSP) and the thickness of pulmonary arteriolar wall were measured from normoxic control, vehicle- and melatonin-treated hypoxic rats exposed to 10% O2 for 14 days. Levels of markers for oxidative stress (malondialdhyde) and inflammation (tumor necrosis factor-α (TNFα), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2)) and the expressions of total endothelial NO synthase (eNOS) and phosphorylated eNOS at serine1177 (ser1177) were determined in the lung tissue. We found that the RVSP and the thickness of the arteriolar wall were significantly increased in the vehicle-treated hypoxic animals with elevated levels of malondialdhyde and mRNA expressions of the inflammatory mediators, when compared with the normoxic control. In addition, the phosphorylated eNOS (ser1177) level was significantly decreased, despite an increased eNOS expression in the vehicle-treated hypoxic group. Melatonin treatment significantly attenuated the levels of RVSP, thickness of the arteriolar wall, oxidative and inflammatory markers in the hypoxic animals with a marked increase in the eNOS phosphorylation in the lung. These results suggest that melatonin attenuates pulmonary hypertension by antagonizing the oxidative injury and restoration of NO production.
Highlights
Chronic hypoxia (CH) induces pulmonary hypertension, pulmonary vascular remodeling and polycythemia in humans and experimental animals [1,2,3]
Pro-inflammatory mediators could be involved in CH-induced pulmonary hypertension because circulating tumor necrosis factor-α (TNFα) level was elevated in chronic obstructive pulmonary disease (COPD) patients [10]
We examined the hypothesis that daily administration of melatonin could mitigate the pulmonary hypertension and vascular remodeling induced by chronic hypoxia via its antagonistic effects against oxidative stress and inflammation, leading to an increase in the phosphorylated endothelial NO synthase (eNOS)
Summary
Chronic hypoxia (CH) induces pulmonary hypertension, pulmonary vascular remodeling and polycythemia in humans and experimental animals [1,2,3]. Recent studies have shown that melatonin treatment could elevate the NO availability in the lungs of newborn sheep at high altitude [24] and alleviate the severe pulmonary hypertension induced by monocrotaline [25] or intermittent hypoxia [26] in rats It is unclear whether the melatonin treatment might ameliorate the pulmonary hypertension induced by chronic hypoxia, which is clinical relevance to the pathophysiological cascade in COPD patients. We examined the hypothesis that daily administration of melatonin could mitigate the pulmonary hypertension and vascular remodeling induced by chronic hypoxia via its antagonistic effects against oxidative stress and inflammation, leading to an increase in the phosphorylated eNOS (ser1177)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
