Abstract
In chronic diseases, hypoxia and physical inactivity are associated with atherosclerosis progression. In contrast, a lower mortality from coronary artery disease and stroke is observed in healthy humans residing at high altitude in hypoxic environments. Eleven young, male volunteers completed the following 10-day campaigns in a randomized order: hypoxic ambulatory, hypoxic bed rest and normoxic bed rest. Before intervention, subjects were evaluated in normoxic ambulatory condition. Normobaric hypoxia was achieved in a hypoxic facility simulating 4000 m of altitude. Following hypoxia, either in bed rest or ambulatory condition, markers of cardiometabolic risk shifted toward a more atherogenic pattern consisting of: (a) lower levels of total HDL cholesterol and HDL2 sub-fraction and decreased hepatic lipase; (b) activation of systemic inflammation, as determined by C-reactive protein and serum amyloid A; (c) increased plasma homocysteine; (d) decreased delta-5 desaturase index in cell membrane fatty acids, a marker of insulin sensitivity. Bed rest and hypoxia additively decreased total HDL and delta-5 desaturase index. In parallel to the pro-atherogenic effects, hypoxia activated selected anti-atherogenic pathways, consisting of increased circulating TNF-related apoptosis-inducing ligand (TRAIL), a protective factor against atherosclerosis, membrane omega-3 index and erythrocyte glutathione availability. Hypoxia mediated changes in TRAIL concentrations and redox glutathione capacity (i.e., GSH/GSSG ratio) were greater in ambulatory conditions (+34 ± 6% and +87 ± 31%, respectively) than in bed rest (+17 ± 7% and +2 ± 27% respectively). Hypoxia-induced cardiometabolic risk is blunted by moderate level of physical activity as compared to bed rest. TRAIL and glutathione redox capacity may contribute to the positive interaction between physical activity and hypoxia.Highlights:– Hypoxia and bed rest activate metabolic and inflammatory markers of atherogenesis.– Hypoxia and physical activity activate selected anti-atherogenic pathways.– Hypoxia and physical activity positive interaction involves TRAIL and glutathione.
Highlights
The association of hypoxia with decreased physical activity is frequently observed in patients affected by chronic cardiopulmonary pathologies, such as COPD, pulmonary fibrosis, OSAS or heart failure
In agreement with the kinetic results, we found that hypoxia directly increased both the modulatory and catalytic subunits of glutamate cysteine ligase, the key enzyme for glutathione synthesis, as determined by western blot in erythrocytes
In agreement with recent evidence (Debevec et al, 2017), we suggest that moderate physical activity can attenuate hypoxiainduced oxidative stress, as shown by the glutathione redox status
Summary
The association of hypoxia with decreased physical activity is frequently observed in patients affected by chronic cardiopulmonary pathologies, such as COPD, pulmonary fibrosis, OSAS or heart failure. Most of these conditions are characterized by excess mortality due to atherosclerosis (Roversi et al, 2014). While the link between physical inactivity and cardiovascular risk is well established (Biolo et al, 2005a); hypoxia can activate both pro- and anti-atherogenic pathways, involving the immune response, redox balance, lipid metabolism and insulin sensitivity (Faeh et al, 2009; Roversi et al, 2014). We have determined the circulating levels of TRAIL (Biolo et al, 2012), which are potentially
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