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Hydrogen Attenuates Chronic Intermittent Hypoxia-Induced Cardiac Hypertrophy by Regulating Iron Metabolism
Jixian Song1,2, Qi Chen1,2, Shan Xu1,2,3
1Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China.
Insights
Hydrogen gas (H₂) effectively combats cardiac hypertrophy caused by chronic intermittent hypoxia (CIH) in mice. This study shows H₂ ameliorates cardiac damage by modulating iron metabolism and reducing oxidative stress.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Oxidative Stress and Metabolism
Background:
- Chronic intermittent hypoxia (CIH) is a condition linked to cardiac hypertrophy, a significant risk factor for cardiovascular diseases.
- Iron metabolism plays a critical role in cellular function and can be dysregulated under hypoxic conditions, potentially contributing to cardiac pathology.
- Hydrogen (H₂) is recognized for its antioxidant properties and potential therapeutic benefits in various conditions.
Purpose of the Study:
- To investigate the protective effects of hydrogen (H₂) against chronic intermittent hypoxia (CIH)-induced cardiac hypertrophy in a mouse model.
- To elucidate the role of H₂ in modulating iron metabolism and oxidative stress pathways within the myocardium during CIH.
Main Methods:
- C57BL/6N mice were exposed to CIH and treated with H₂ inhalation for five weeks.
- Cardiac and mitochondrial function, reactive oxygen species (ROS), and iron levels were assessed.
- H9C2 cells were subjected to intermittent hypoxia (IH) and H₂ treatment to study cellular mechanisms.
Main Results:
- H₂ significantly ameliorated CIH-induced cardiac hypertrophy, pathological alterations, and mitochondrial damage (p < 0.05).
- H₂ suppressed oxidative injury by reducing inducible nitric oxide synthase (i-NOS) and 4-hydroxynonenal (4-HNE) levels (p < 0.05, p < 0.01).
- H₂ decreased myocardial iron levels by upregulating ferroportin 1 (FPN1) and downregulating transferrin receptor 1 (TfR1), DMT1(+ire), and FTL (p < 0.01, p < 0.05).
Conclusions:
- Hydrogen gas demonstrates significant cardioprotective effects against CIH-induced cardiac hypertrophy in mice.
- H₂ exerts its benefits by mitigating oxidative stress and re-regulating iron metabolism through key protein and mRNA modulations.
- These findings suggest H₂ holds therapeutic potential for preventing cardiac hypertrophy associated with iron toxicity and hypoxia.
Abstract:
The present study aimed to investigate the impact of hydrogen (H2) 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 + H2, and H2. The mice were exposed to CIH (21-5% FiO2, 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 H2. Firstly, we found H2 had a notable impact on cardiac hypertrophy, ameliorated pathological alterations and mitochondrial morphology induced by CIH (p < 0.05). Secondly, H2 exhibited a suppressive effect on oxidative injury by decreasing levels of inducible nitric oxide synthase (i-NOS) (p < 0.05) and 4-hydroxynonenal (4-HNE) (p < 0.01). Thirdly, H2 demonstrated a significant reduction in iron levels within myocardial cells through the upregulation of ferroportin 1 (FPN1) proteins (p < 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 (p < 0.05). Simultaneously, H2 exhibited the ability to decrease the levels of Fe2+ and ROS in H9C2 cells exposed to IH (p < 0.05). Moreover, H2 mediated the expression of hepcidin, hypoxia-inducible factor-1α (HIF-1α) (p < 0.01), and iron regulatory proteins (IRPs), which might be involved in the regulation of iron-related transporter proteins. These results suggested that H2 may be beneficial in preventing cardiac hypertrophy, a condition associated with reduced iron toxicity.
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