Constitutive hydrogen inhalation prevents vascular remodeling via reduction of oxidative stress

Abstract

Molecular hydrogen is thought to have an inhibitory effect on oxidative stress, thereby attenuating the onset and progression of various diseases including cardiovascular disease; however, few reports have assessed the preventive effect of constitutive inhalation of hydrogen gas on of vascular remodeling. Here, we investigated the effect of constitutive inhalation of hydrogen gas on vascular neointima formation using a cuff-induced vascular injury mouse model. After constitutive inhalation of compressed hydrogen gas (O2 21%, N2 77.7%, hydrogen 1.3%) or compressed air only (O 2 21%, N 2 79%) by C57BL/6 mice for 2 weeks from 8 weeks of age in a closed chamber, inflammatory cuff injury was induced by polyethylene cuff placement around the femoral artery under anesthesia, and hydrogen gas administration was continued until sampling of the femoral artery. Neointima formation, accompanied by an increase in cell proliferation, was significantly attenuated in the hydrogen group compared with the control group. NADPH oxidase NOX1 downregulation in response to cuff injury was shown in the hydrogen group, but the expression levels of NADPH oxidase subunits, p40phox and p47phox, did not differ significantly between the hydrogen and control groups. Although the increase in superoxide anion production did not significantly differ between the hydrogen and control groups, DNA damage was decreased as a result of reduction of reactive oxygen species such as hydroxyl radical (�OH) and peroxynitrite (ONOO-) in the hydrogen group. These results demonstrate that constitutive inhalation of hydrogen gas attenuates vascular remodeling partly via reduction of oxidative stress, suggesting that constitutive inhalation of hydrogen gas at a safe concentration in the living environment could be an effective strategy for prevention of vascular diseases such as atherosclerosis.

ONOO−‐mediated oxidative modification of extracellular matrix aggravates atherosclerosis by affecting biological behaviors of vascular smooth muscle cells

“…Moreover, ONOO − is accepted as a prototype reactive nitrogen species being able to mediate the early progression of the atherosclerotic lesion (Patel et al, 2000). Reduction of ONOO − can decrease the DNA damage in vascular injury and thus aids in attenuating vascular remodeling, potentially serving as an effective strategy for the prevention of vascular diseases, such as AS (Kiyoi et al, 2020).…”

Hydrogen, a Novel Therapeutic Molecule, Regulates Oxidative Stress, Inflammation, and Apoptosis

“…They demonstrated the protective potential of H 2 against I/R injury, where H 2 reduced oxidative stress and scavenged ·OH and ONOO − , acting as an electron donor for ROS molecules, but the direct ROS scavenging effect of H 2 is only confirmed in the acellular experiment. Similarly, after administration with 1.3% H 2 gas inhalation for 2 weeks in vasculitis mice, the tissue damage was decreased as a result of reduction of ·OH and ONOO − (Kiyoi et al, 2020 ). By regulating their concentration, they also prevent the production of hydroxyl radicals as they can be converted to •OH radicals via the Haber-Weiss and Fenton reaction in the presence of catalytically active metals such as Fe 2+ and Cu + (Huang, 2016 ).…”

Role of Molecular Hydrogen in Ageing and Ageing-Related Diseases

“…(2) H 2 Directly Scavenges ONOO − . Compared to •OH, the half-life of ONOO − is long, which has a greater chance to react with H 2 at the lesion site [ 28 , 29 ]. In addition, H 2 inhibits the generation of nitrotyrosine, which reflects the generation of ONOO − [ 30 ].…”