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.
Highlights
PBS Octanoic acid Linolenic acid stimulating the hormonal expression of ghrelin[10] and fibroblast growth factor 21 (FGF21)[11], respectively
Our results suggested that low concentrations of H2 modulated Ca2+ signal transduction and regulated gene expression by modifying the production of oxidized phospholipid species
H2 seemed to be retained significantly longer in the unsaturated fatty acid than in the saturated fatty acids (Fig. 1c), this difference in retention time might be attributed to the difference in the number of carbons
Summary
PBS Octanoic acid Linolenic acid stimulating the hormonal expression of ghrelin[10] and fibroblast growth factor 21 (FGF21)[11], respectively. H2 relieves inflammation by decreasing pro-inflammatory cytokines[12]. It is difficult to explain the molecular mechanisms by which H2 exerts these functions by conventional concepts alone. To understand the molecular mechanisms by which H2 exerts these multiple functions, it is essential to identify the primary targets of H2 that modulate signal transduction and gene expression. In this study, we aimed to elucidate one of the molecular mechanisms by which H2 mediates signal transduction and gene expression. Our results suggested that low concentrations of H2 modulated Ca2+ signal transduction and regulated gene expression by modifying the production of oxidized phospholipid species
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