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

We previously showed that H 2 acts as a novel antioxidant to protect cells against oxidative stress. Subsequently, numerous studies have indicated the potential applications of H 2 in therapeutic and preventive medicine. Moreover, H 2 regulates various signal transduction pathways and the expression of many genes. However, the primary targets of H 2 in the signal transduction pathways are unknown. Here, we attempted to determine how H 2 regulates gene expression. In a pure chemical system, H 2 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 H 2 . H 2 modified the chemical production of the autoxidized phospholipid species in the cell-free system. Exposure of cultured cells to the H 2 -dependently autoxidized phospholipid species reduced Ca 2+ signal transduction and mediated the expression of various genes as revealed by comprehensive microarray analysis. In the cultured cells, H 2 suppressed free radical chain reaction-dependent peroxidation and recovered the increased cellular Ca 2+ , resulting in the regulation of Ca 2+ -dependent gene expression. Thus, H 2 might regulate gene expression via the Ca 2+ signal transduction pathway by modifying the free radical-dependent generation of oxidized phospholipid mediators.