Hydrogen and Oxygen Mixture to Improve Cardiac Dysfunction and Myocardial Pathological Changes Induced by Intermittent Hypoxia in Rats

Obstructive sleep apnea (OSA) can cause intermittent changes in blood oxygen saturation, resulting in the generation of many reactive oxygen species (ROS). To discover new antioxidants and clarify the endoplasmic reticulum (ER) stress involved in cardiac injury in OSA, we established a chronic intermittent hypoxia (CIH) rat model with a fraction of inspired O(2) (FiO(2)) ranging from 21% to 9%, 20 times/h for 8 h/day, and the rats were treated with H(2)-O(2) mixture (67% hydrogen and 33% oxygen) for 2 h/day for 35 days. Our results showed that H(2)-O(2) mixture remarkably improved cardiac dysfunction and myocardial fibrosis. We found that H(2)-O(2) mixture inhalation declined ER stress-induced apoptosis via three major response pathways: PERK-eIF2α-ATF4, IRE 1-XBP1, and ATF 6. Furthermore, we revealed that H(2)-O(2) mixture blocked c-Jun N-terminal kinase- (JNK-) MAPK activation, increased the ratio of Bcl-2/Bax, and inhibited caspase 3 cleavage to protect against CIH-induced cardiac apoptosis. In addition, H(2)-O(2) mixture considerably decreased ROS levels via upregulating superoxide dismutase (SOD) and glutathione (GSH) as well as downregulating NADPH oxidase (NOX 2) expression in the hearts of CIH rats. All the results demonstrated that H(2)-O(2) mixture significantly reduced ER stress and apoptosis and that H(2) might be an efficient antioxidant against the oxidative stress injury induced by CIH.