| Co-Investigator(Kenkyū-buntansha) |
SAITOH Shuichi Fukushima Medical University, First Department of Internal Medicine, Assistant, 医学部, 助手 (20274962)
YAOITA Hiroyuki Fukushima Medical University, First Department of Internal Medicine, Assistant Professor, 医学部, 講師 (50264544)
ISHIBASHI Toshiyuki Fukushima Medical University, First Department of Internal Medicine, Associate Professor, 医学部, 助教授 (00223024)
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| Research Abstract |
This project aimed to investigate the signaling pathway involved in RhoA activation of endothelid dysfunction and the therapeutic strategy. Oxidized LDL (oxLDL) and monocyte adhesion induce and accelerate endothelial dysfunction.
We found that lysophosphatidylcholine, an atherogenic compound of oxLDL, rapidly activates RhoA as well as calcium signaling, suggesting the involvement of RhoA is calcium mobilization and influx (Circuladtion 2002 ; 105). In isolated cardiomyocytes, we reported that RhoA is involved in nonselective cation current (Mol. Pharmacol. 2002 ; 62). In monocyte adhesion to endothelial cells, RhoA was activated in endotheliat cells within 15 minutes after adding monocytes and upstream of NF-κB in gene regulation of tissue factor (Arterioscler Thromb Vasc Biol 2003 ; 23). We also found that RhoA plays a crucial role in eNOS downregulation and that membrane-bound type of matrix metalloproteinase is upstream of RhoA. In addition, we showed that in cultured hum an monocyte
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s, RhoA plays an important role in the regulation of thrombosis-related genes such as tissue factor and plasminogen activator inhibitor-1 (Atherosclerosis, 2002 ; 1 63, and Biochemica et Biophysica Acta, 2002 ; 1590). Statins have been shown to have beneficial effects in this study.
We developed a novel coronary spasm pocine induced by repeated epicardal endothelid denudation. It was found that repeated endothetial injuries induce a spontaneous coronary microvasvular spasm and reactive oxygen species play a role in coroncry microvascular spasm induced by endothelial injuries (Coronary Artery Disease. 2004 ; 15 (3), and Coronary Artery Disease, 2004 ; 15 (1)). Moreover, we have shown that blockade of rennin-angiotensin system is effective to prevent the remodeling of ischemic myocardium in a rat coronary stenosis model (American Journal of Physiology, 2003 : 285).
The present study shows that RhoA activation plays a crucial role in endothelial dysfunction and that statins are a candidate to treat endothelial dysfunction. Furtherstudy is neededto clarify the mechanism of upstream of RhoA in endothelial dysfunction which may establish new therapeutic strategy. Less
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