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

摘要

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.