| Co-Investigator(Kenkyū-buntansha) |
OMURA Takashi Osaka City University, Graduate School of Medicine, Associate Professor, 大学院・医学研究科, 助手 (70295707)
YOSHIYAMA Minoru Osaka City University, Graduate School of Medicine, Associate Professor, 大学院・医学研究科, 助教授 (30240956)
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| Research Abstract |
To elucidate the roles of myocardial AP-1 activities, dominant negative mutant of c-Jun (DNJun) was overexpressed in cultured rat neonatal ventricular myocytes by adenovirus vector. Cardiomyocytes were treated with 100 nmol/L endothelin 1 (ET) and 10 □mol/L phenylephrine (PE) to induce myocardial cell hypertrophy. At 48 h after stimulation, ET and PE significantly increased incorporation of ^3H-phynylalanine, cell size and mRNA expression of ANP and BNP. Adenovirus carrying DNJun prevented the transcriptional activation of the AP-1 by ET and PE, using AP-1 reporter enzyme firefly luciferase assay. Moreover, DNJun prevented the increase in incorporation of ^3H-phenylalanine, cell size and the mRNA expression of ANP and BNP by ET and PE. Moreover, angiotensin II-induced MCP-1 expression was examined in cultured cardiac fibroblasts. Dominant negative mutant (DN) of ASK-1, DN-p38MAPK and pyrrolidine dithiocarbamate inhibited the expression. The increased expression by wild-type ASK-1 was inhibited by DN-p38MAPK and pyrrolidine dithiocarbamate. ASK-1 followed by p38MAPK and NF-kB is involved in angiotensin II-induced MCP-1 expression. Furthermore, we investigated the effects of cell transplantation of VEGF-expressing mesenchymal stem cells (MSCs) on myocardial infarction (MI). The human VEGF and/or LacZ gene was transfected to cultured MSCs of Lewis rats by adenoviral vector. MSCs were injected into syngeneic rat hearts one hour after left coronary artery occlusion. At 28 days after MI, infarct size, left ventricular dimensions, ejection fraction, E/A ratio and capillary density of infarct region were most improved in the VEGF expressing MSCs group. In conclusion, this combined strategy of cell transplantation with gene therapy could be a useful therapy for the treatment of MI.
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