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

内皮功能障碍的信号通路和治疗策略：小GTP结合蛋白RhoA的作用和HMG-CoA还原酶抑制剂的有益作用

• 批准号: 14370232
• 负责人: MARUYAMA Yukio
• 金额: $ 4.54万
• 依托单位: Fukushima Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370232/
• 关键词: endothelial dysfunction; RhoA; geranylgeranylation; monocyteadhesion; oxidized LDL; tissue factor; plasminogen activator inhibitor-1; NF-κB; calcium; 活性酸素種; 組織因子; 血管内皮細胞

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

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

项目成果

石橋敏幸: "高脂血症"高脂血症治療薬のPleiotropic effects.新しい診断と治療のABC13代謝1. 212-220 (2003)

石桥敏之：《高脂血症治疗药物ABC13代谢的多效性》1. 212-220 (2003)。

Aikawa K, Saitoh S, Maruyama Y, et al.: "Effects of antioxidants on coronary microvascular spasm induced by epicardial coronary artery endothelial injury pigs"Coronary Artery Disease. 15・1. 21-30 (2004)

Aikawa K、Saitoh S、Maruyama Y 等：“抗氧化剂对心外膜冠状动脉内皮损伤猪引起的冠状动脉微血管痉挛的影响” 冠状动脉疾病 15・1。

石橋敏幸, 阪本貴之, 大河原浩, 杉本浩一, 坂本信雄, 横山恵子, 寺本民生, 丸山幸夫: "ピタバスチンは酸化LDL存在下において単球および血管内皮細胞共培養系における組織因子発現を抑制する"Therapeutic Research. 24・9. 1732-1738 (2003)

Toshiyuki Ishibashi、Takayuki Sakamoto、Hiroshi Okawara、Koichi Sugimoto、Nobuo Sakamoto、Keiko Yokoyama、Tamio Teramoto、Yukio Maruyama：“Pitabastin 在氧化 LDL 存在的情况下抑制单核细胞和血管内皮细胞共培养系统中的组织因子表达”治疗研究。 24・9。1732-1738（2003）

Aikawa K, Saitoh S, Maruyama Y et al.: "Effects of antioxidants on coronary microvascular spasm induced by epicardial coronary artery endothelial injury in pigs."Coronary Artery Disease. 15・1. 21-30 (2004)

Aikawa K、Saitoh S、Maruyama Y 等人：“抗氧化剂对猪心外膜冠状动脉内皮损伤引起的冠状动脉微血管痉挛的影响”，《冠状动脉疾病》15・1。

Ishibashi T: "Integral role of RhoA activation in monocyte adhesion-triggered tissue factor expression in endothelial cells"Arterioscler. Thromb. Vasc. Biol.. (in press). (2003)

Ishibashi T：“RhoA 激活在内皮细胞中单核细胞粘附触发的组织因子表达中的整体作用”Arterioscler。