Molecular hydrogen regulates gene expression by modifying the free radical chain reaction-dependent generation of oxidized phospholipid mediators

Abstract

We previously showed that H2 acts as a novel antioxidant to protect cells against oxidative stress. Subsequently, numerous studies have indicated the potential applications of H2 in therapeutic and preventive medicine. Moreover, H2 regulates various signal transduction pathways and the expression of many genes. However, the primary targets of H2 in the signal transduction pathways are unknown. Here, we attempted to determine how H2 regulates gene expression. In a pure chemical system, H2 gas (approximately 1%, v/v) suppressed the autoxidation of linoleic acid that proceeds by a free radical chain reaction, and pure 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (PAPC), one of the major phospholipids, was autoxidized in the presence or absence of H2. H2 modified the chemical production of the autoxidized phospholipid species in the cell-free system. Exposure of cultured cells to the H2-dependently autoxidized phospholipid species reduced Ca2+ signal transduction and mediated the expression of various genes as revealed by comprehensive microarray analysis. In the cultured cells, H2 suppressed free radical chain reaction-dependent peroxidation and recovered the increased cellular Ca2+, resulting in the regulation of Ca2+-dependent gene expression. Thus, H2 might regulate gene expression via the Ca2+ signal transduction pathway by modifying the free radical-dependent generation of oxidized phospholipid mediators.

Study details

Article type

Original Research

Dose comparison

The study compared the effects of different concentrations of H2 (0.3%, 1.3%, 5%) on lipid peroxidation, Ca2+ signaling, and gene expression.

Dose-dependent effect

Yes

Outcome

Positive

Findings

Low concentrations of molecular hydrogen (H2) modulate Ca2+ signal transduction and regulate gene expression by modifying the production of oxidized phospholipid species, likely through suppression of free radical chain reactions. H2 reduces lipid peroxidation, alters Ca2+ signaling, and affects the expression of genes involved in signaling pathways, particularly those regulated by NFAT and CREB transcription factors.