Establishment of a role of reactive oxygen species as a second messenger

点击翻译按钮获取中文摘要

We examined the role of reactive oxygen species (ROS) as a second messenger using rat neonatal cardiac myocytes and fibroblasts. When cardiac myocytes were stimulated by angiotensin II, three MAP kinases (ERK, JNK and p38 MAPK) were activated. Among three MAP kinases, JNK and p38 MAPK but not ERK were activated in a ROS-dependent manner. We examined the signaling pathway leading to JNK activation in detail, and have found the following results. Heterotrimeric G_<α12> and G_<α13> that belong to G_<12> family G proteins were directly activated by angiotensin receptor stimulation, and G12 family G proteins activated small G protein Rho. Then, Rho activated another small G protein Rae, and Rac increased NADPH oxidase that resulted in ROS production. Inhibition of ROS production suppressed hypertrophy induced by angiotensin stimulation. These results suggested that ROS indirectly mediated hypertrophic responses through JNK and p38 MAPK activation. On the other hand, it is believed that cardiac fibroblasts are involved in fibrosis by production of cytokines through activation of NFAT and other transcriptional factors. When cardiac fibroblasts were stimulated by angiotensin II, NFAT transcriptional activation was observed in a ROS-dependent manner. However, nuclear translocation of NFAT was not affected by elimination of ROS. We analyzed NEAT activation pathway and demonstrated that G_<α12>- and G_<α13>-mediated ROS production is involved in JNK activation, and JNK activated another factor that is necessary for NFAT-dependent transcriptional activation. These results indicated that G_<12> family G proteins regulate ROS production, and ROS play an essential role of JNK activation.