A New Approach for the Prevention and Treatment of Cardiovascular Disorders. Molecular Hydrogen Significantly Reduces the Effects of Oxidative Stress

Abstract

Cardiovascular diseases are the most common causes of morbidity and mortality worldwide. Redox dysregulation and a dyshomeostasis of inflammation arise from, and result in, cellular aberrations and pathological conditions, which lead to cardiovascular diseases. Despite years of intensive research, there is still no safe and effective method for their prevention and treatment. Recently, molecular hydrogen has been investigated in preclinical and clinical studies on various diseases associated with oxidative and inflammatory stress such as radiation-induced heart disease, ischemia-reperfusion injury, myocardial and brain infarction, storage of the heart, heart transplantation, etc. Hydrogen is primarily administered via inhalation, drinking hydrogen-rich water, or injection of hydrogen-rich saline. It favorably modulates signal transduction and gene expression resulting in suppression of proinflammatory cytokines, excess ROS production, and in the activation of the Nrf2 antioxidant transcription factor. Although H₂ appears to be an important biological molecule with anti-oxidant, anti-inflammatory, and anti-apoptotic effects, the exact mechanisms of action remain elusive. There is no reported clinical toxicity; however, some data suggests that H₂ has a mild hormetic-like effect, which likely mediate some of its benefits. The mechanistic data, coupled with the pre-clinical and clinical studies, suggest that H₂ may be useful for ROS/inflammation-induced cardiotoxicity and other conditions.

Keywords: heart transplantation; ischemia/reperfusion injury; molecular hydrogen; oxidative stress; radiation-induced heart disease.

Figure 1

Production of ROS: effect of antioxidants and selective action of H₂. Schematic reactions of ROS production by action of enzymes during respiration in mitochondria. Green color represents non-radical molecules, red color represents ROS created from normal respiration, yellow color indicates action of H₂.

Figure 2

Mechanism of H₂ action: transcription and production of innate antioxidants upon entry into cell cytoplasm, release and accumulation of Nrf2 and its translocation into the nucleus. CAT = catalase, SOD = superoxide dismutase, GTP = glutathione peroxidase.

Figure 3

Effect of molecular hydrogen on irradiation-induced lipid peroxidation and inflammation. The marker of oxidative stress, malondialdehyde (MDA), was elevated in blood plasma after irradiation of rat myocardium. Application of molecular hydrogen (H₂) significantly decreased the levels of MDA. Myocardium irradiation increased levels of the inflammatory marker TNF-α in the rat´s heart tissue. Significant reduction of TNF-α was observed after H₂ treatment. OS = oxidative stress, H₂ = molecular hydrogen. Values are means ± SD, n = 5, *: p < 0.05. Modified from reference [8].

Figure 4

Mechanisms of molecular hydrogen action in condition of increased oxidative stress. Molecular hydrogen has been demonstrated to provide protective effects via several mechanisms including antioxidant, anti-inflammatory and cytoprotective actions, as well as via signal modulation.