Signaling pathway and therapeutic strategy of endothelial dysfunction : role of small GTP-binding protein RhoA and beneficial effects of HMG-CoA reductase inhibitor

本课题旨在探讨内皮功能障碍时RhoA激活的信号通路及其治疗策略。氧化低密度脂蛋白(OxLDL)和单核细胞黏附诱导和加速内皮功能障碍。我们发现，oxLDL的致动脉粥样硬化化合物溶血磷脂酰胆碱能迅速激活RhoA和钙信号，提示RhoA参与了钙动员和内流(Circuladtion 2002；105)。在分离的心肌细胞中，我们报道了RhoA参与非选择性阳离子电流。药水。2002年；62)。在单核细胞与内皮细胞的黏附中，加入单核细胞后15分钟内内皮细胞中RhoA被激活，在组织因子的基因调控中，NF-κB的上游被激活(Arterioscler Thromb VASc Biol 2003；23)。我们还发现RhoA在eNOS下调中起关键作用，膜结合型基质金属蛋白酶位于RhoA的上游。此外，我们还发现在培养的人单核细胞中存在…S，RhoA在组织因子和纤溶酶原激活物抑制物-1等血栓形成相关基因的调控中发挥了重要作用(Athersis，2002；1 63，and BioChemica et BiPhysica Acta，2002；1590)。在这项研究中，他汀类药物被证明是有益的。我们开发了一种新的冠状动脉痉挛药物，这种药物是通过反复剥离心外膜内皮诱导的。研究发现，反复内皮损伤可诱发自发性冠脉微血管痉挛，而活性氧在内皮损伤所致冠脉微血管痉挛(冠状动脉疾病)中起一定作用。2004年；15(3)；和冠状动脉疾病，2004；15(1))。此外，我们还证明了阻断肾素-血管紧张素系统可以有效地防止大鼠冠状动脉狭窄模型中缺血心肌的重构(American Journal of Physiology，2003：285)。目前的研究表明，RhoA的激活在内皮功能障碍中起着关键作用，他汀类药物是治疗内皮功能障碍的候选药物。RhoA上游在血管内皮细胞功能障碍中的作用机制有待进一步研究，这可能会建立新的治疗策略。较少

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 … More 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