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

Abstract

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 O2 (FiO2) ranging from 21% to 9%, 20 times/h for 8 h/day, and the rats were treated with H2-O2 mixture (67% hydrogen and 33% oxygen) for 2 h/day for 35 days. Our results showed that H2-O2 mixture remarkably improved cardiac dysfunction and myocardial fibrosis. We found that H2-O2 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 H2-O2 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, H2-O2 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 H2-O2 mixture significantly reduced ER stress and apoptosis and that H2 might be an efficient antioxidant against the oxidative stress injury induced by CIH.

Hydrogen: A Novel Option in Human Disease Treatment

“…H 2 can also downregulate ROS directly or as a regulator of a gas-mediated signal. Further, by upregulating the expression of SOD and glutathione (GSH), and downregulating the expression of NADPH oxidase (NOX2) [ 18 ], H 2 can significantly reduce ROS. Another study [ 19 ] showed that H 2 mainly blocks the phosphorylation of ASK1 and its downstream signal molecules p38 MAPK or c-Jun N-terminal kinase (JNK), but not the production of ROS by NADPH oxidase.…”

“…The accumulation of unfolded protein in the endoplasmic reticulum (ER) caused by pathological stress can trigger ER stress. Zhao et al [ 18 ] observed that hydrogen inhalation significantly reduced the ER stress-related protein and alleviated tissue damage in myocardial I/R injury and later found that a mixture of H 2 and O 2 can block endoplasmic reticulum stress via the PKR-like ER-localized eIF2 α kinase-eukaryotic initiation factor 2 alpha-activating transcription factor 4 (PERK-eIF2 α -ATF 4), inositol-requiring enzyme 1-X-box binding protein 1 (IRE 1-XBP1), and ATF 6 pathways. A study of the relationship between H 2 and ER stress in rats with I/R injury found that H 2 induced the decrease of GRP78 and TNF receptor-associated factor 2 (TRAF2) expression [ 25 ], suggesting that the protective effects of H 2 on myocardial I/R injury are related to decreased ER stress.…”

Verification of Resveratrol Inhibits Intestinal Aging by Downregulating ATF4/Chop/Bcl-2/Bax Signaling Pathway: Based on Network Pharmacology and Animal Experiment

“…Evidence have suggested that ATF4/Chop/Bcl-2/Bax signaling pathway is involved in multiple metabolic functions of the body, such as endoplasmic reticulum stress, apoptosis, autophagy, ect ( Yoneshima et al., 2016 ; Liu H. et al., 2020 ; Sharifi et al., 2020 ; Zeng et al., 2020 ). The expression of SOD, GSH-Px, CAT, AE in antioxidant enzymes and the level of ATF4, CHOP, BCL-2, and BAX in ATF4/Chop/Bcl-2/Bax signaling pathways were simultaneously found aberrant expression in endoplasmic reticulum stress and apoptosis ( Gao et al., 2017 ; Xiao et al., 2019 ; Zhao et al., 2019 ; Li et al., 2020 ). Moreover, it was found that NaHS restored the decreased activity of antioxidant enzymes such as GSH, SOD, and CAT in the aging model by regulating to PI3K/AKT signaling pathways ( Chen et al., 2017 ).…”

Biological Network Model of Effect of Chronic Intermittent Hypoxia on Spermatogenesis in Rats

“…The total time of intermittent hypoxia was 120 s. The rats had water and food in the cabin and could eat normally. Studies have shown that the method of intermittent hypoxia used in the present study can cause arterial oxygen saturation in rats to fluctuate periodically with the intermittent change of oxygen concentration in the cabin [ 13 ]. The intermittent hypoxia phase of the experiment was conducted daily from 9 am to 5 pm, 8 h/day, and lasted for 6 weeks.…”