Hydrogen Attenuates Chronic Intermittent Hypoxia-Induced Cardiac Hypertrophy by Regulating Iron Metabolism

• Published in: Current issues in molecular biology Vol. 45; no. 12; pp. 10193 - 10210
• Main Authors: Song, Jixian, Chen, Qi, Xu, Shan, Gou, Yujing, Guo, Yajing, Jia, Cuiling, Zhao, Chenbing, Zhang, Zhi, Li, Boliang, Zhao, Yashuo, Ji, Ensheng
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-12-2023
• Subjects: cardiac hypertrophy; chronic intermittent hypoxia; ferroportin 1; hydrogen; mitochondrial dysfunction; obstructive sleep apnea; obstructive sleep apnea; ferroportin 1; hepcidin; chronic intermittent hypoxia; mitochondrial dysfunction; hydrogen; cardiac hypertrophy
• ISSN: 1467-3045; 1467-3037; 1467-3045
• DOI: 10.3390/cimb45120636

The present study aimed to investigate the impact of hydrogen (H
) on chronic intermittent hypoxia (CIH)-induced cardiac hypertrophy in mice by modulating iron metabolism. C57BL/6N mice were randomly allocated into four groups: control (Con), CIH, CIH + H
, and H
. The mice were exposed to CIH (21-5% FiO
, 3 min/cycle, 8 h/d), and received inhalation of a hydrogen-oxygen mixture (2 h/d) for 5 weeks. Cardiac and mitochondrial function, levels of reactive oxygen species (ROS), and iron levels were evaluated. The H9C2 cell line was subjected to intermittent hypoxia (IH) and treated with H
. Firstly, we found H
had a notable impact on cardiac hypertrophy, ameliorated pathological alterations and mitochondrial morphology induced by CIH (
< 0.05). Secondly, H
exhibited a suppressive effect on oxidative injury by decreasing levels of inducible nitric oxide synthase (i-NOS) (
< 0.05) and 4-hydroxynonenal (4-HNE) (
< 0.01). Thirdly, H
demonstrated a significant reduction in iron levels within myocardial cells through the upregulation of ferroportin 1 (FPN1) proteins (
< 0.01) and the downregulation of transferrin receptor 1 (TfR1), divalent metal transporter 1 with iron-responsive element (DMT1(+ire)), and ferritin light chain (FTL) mRNA or proteins (
< 0.05). Simultaneously, H
exhibited the ability to decrease the levels of Fe
and ROS in H9C2 cells exposed to IH (
< 0.05). Moreover, H
mediated the expression of hepcidin, hypoxia-inducible factor-1α (HIF-1α) (
< 0.01), and iron regulatory proteins (IRPs), which might be involved in the regulation of iron-related transporter proteins. These results suggested that H
may be beneficial in preventing cardiac hypertrophy, a condition associated with reduced iron toxicity.