MASUYAMA Tohru Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70273670)
SATO Hideyuki Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70167435)
KUZUYA Tsunehiko Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (80150340)
SATO Hiroshi Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (10294092)
KITAKAZE Masafumi Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (20294069)
西田 昌司 大阪大学, 医学系研究科, 助手 (40283783)
|Budget Amount *help
¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2000: ¥9,000,000 (Direct Cost: ¥9,000,000)
In response to ischemic stress, oxygen radical has been found to be a key mediator, which subsequently induces anti-oxidant effectors such as adenosine, as well as Mn-SOD.This process should explain how ischemic preconditioning is beneficial for the protection against ischemic stress. We aimed to determine how the exogenous stress induces the protective effects in the heart.
(1) Mechanism of stress resistance induced in the cardiac myocytes.
We used rat cardiac myocytes, endothelial cells and smooth muscle cells as cell model, and treated them with ischemia-reperfusion, heat schock and stretch stress. After treatment, we examined effector molecule such as ecto-5'-nucleatidase and Mn-SOD by measuring their protein expression and activities. Both protein and activities of these molecules were increased. When cardiac cells were overexpressed with each of these molecules, cells over-expressing molecule showed resistance against various stresses.
(2) Intracellular signaling pathways in the cardiac cells in response to stresses.
Oxygen radicals, proposed to be a major mechanism in stress-response, was measured by using fluorescence assay system, and found to be increased in the cytosol after various types of stresses. By the biochemical analysis of intracellular signal molecules, PK-C, MAPK, JNK, P38, and S6 kinase, we found that JNK, P38, and S6 kinase are important for the induction of stress-response signaling. Thus, the final effector such as Mn-SOD should be increased by these molecules.
In conclusion, we determined the intracellular signaling pathway involved in the stress-response. P38 and S6 kinase were identified to be key mediators in this process.