Constitutive hydrogen inhalation prevents vascular remodeling via reduction of oxidative stress.

Takeshi Kiyoi,Masaki Mogi,Erika Takemasa,Naohito Hato,Shuang Liu,Hirotomo Nakaoka,Michael Bader

doi:10.1371/journal.pone.0227582

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 (O2 21%, N2 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.

Highlights

Cardiovascular disease (CVD), including ischemic heart disease, remains the leading cause of health loss and death worldwide [1]
Fluorescence labeling index of 8-OHdG was significantly reduced 0.84-fold in hydrogen group (Hyd) compared with that in control air group (Con) (Fig 6B). These results demonstrated that constitutive inhalation of hydrogen gas at a low concentration attenuated vascular remodeling via reduction of oxidative stress and proliferative signaling
Previous reports on the effects of hydrogen gas inhalation on CVD have focused on clinical application using a rat ischemia and reperfusion (I/R) injury model [12, 20]

Summary

Introduction

Cardiovascular disease (CVD), including ischemic heart disease, remains the leading cause of health loss and death worldwide [1]. It has been suggested that lifestyle-related diseases such as hypertension, diabetes and obesity are involved in the onset of CVD, and disease progression is accompanied by vascular injury due to reactive oxygen species (ROS)-dependent chronic/ persistent oxidative stress [2, 3]. Reduction of oxidative stress by down-regulating ROS could be an approach for prevention of the onset of CVD. Molecular hydrogen has been proved to bring about beneficial effects on the pathophysiology of various diseases through reduction of oxidative stress [7,8,9,10]. It was suggested that molecular hydrogen prevents vascular remodeling in animal models such as ischemia and reperfusion (I/R) injury, vein grafting, carotid balloon injury and cerebral vasospasm of subarachnoid hemorrhage via reduction of oxidative stress [12,13,14,15]

Methods

Results

Conclusion