The Ca-activated K channel as a new therapeutic target for vascular remodeling, and its expressional control mechanism

Ca激活K通道作为血管重塑新治疗靶点及其表达控制机制

• 批准号: 16590656
• 负责人: HASEGAWA Hitoshi
• 金额: $ 2.18万
• 依托单位: Akita University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590656/
• 关键词: L-NAME; vascular remodeling; TRAM34; NFκ-B; imidazole; pyrazole系; clotrimazole; SOCE; SOCE; NFk-B; 血管モデリング

1.In the present study, the inhibition of expression and function of the Ca-activated K channel (IKca) in its involvement in vascular inflammation and subsequent vascular remodeling formation such as cell multiplication and dedifferentiation were investigated as therapeutic targets for vascular lesion formation.2.Analysis of the molecular mechanism of IKca expression control in vascular smooth muscle cells and immune system cells. In order to determine the association between vascular lesion formation in states of cardiovascular disease characterized mainly by hypertension and arteriosclerosis, and IKca expression modification in vascular and immune cells, while also analyzing the possibility of IKca as a new therapeutic target, the following additional investigations were conducted in succession: a) analysis of the molecular mechanism of IKca expression control in vascular smooth muscle cells and immune cells, b) the search for a therapeutic drug that targeted IKca expression in the b … More ase clinical state model of vascular disease.3.Cultured vascular smooth muscle cells from the rat aorta, obtained using the explant method, were cultured under stimulation by angiotensin II and PDGF, for analyses of the association between the expression of BTEB2 and of IKca occurring with phenotype transformation into the proliferative form, and the effects of NO donors and superoxide anions on IKca expression. Increases in BTEB2 and IKca expression were decreased by NO donors and intensified by superoxide anions. The search for a therapeutic drug that targets IKca expression in the base clinical state model of vascular disease4.The relationship between the NFk-B activator, which is a transcription factor sensitive to redox as well as increased superoxide anion production resulting from NO decrease and has a corresponding site on IKca promoters, and IKca expression in smooth muscle and T-lymphocytes was discussed with respect to rats receiving prolonged L-NAME administration. In addition, as indicators for the inhibition of IKca expression and NFkB activation, the efficacies of the following were analyzed: (1) imidazole/pyrazole-type drugs, clotrimazole, TRAM34 (all are selective IKca inhibitors), (2) statin-type drugs, and (3) NS1619. Although all drugs tended to inhibit IKca expression and NFkB activation, no significant differences were observed. (4) The effect of low-molecular-weight heparin, which possesses antiplatelet and anti-inflammatory properties, was investigated using rats that received prolonged L-NAME administration. Low-molecular-weight heparin inhibited the cardiovascular remodeling that occurs with prolonged L-NAME administration, such as pericoronary fibrosis and increased medial smooth muscle hypertrophy. Less

1.本研究以钙激活钾通道（IKca）的表达和功能为靶点，探讨IKca在血管炎症和血管重塑中的作用。2.血管平滑肌细胞和免疫系统细胞IKca表达调控的分子机制。为了确定以高血压和动脉硬化为主要特征的心血管疾病状态下的血管病变形成与血管和免疫细胞中IKca表达修饰之间的关联，同时还分析IKca作为新治疗靶点的可能性，连续进行了以下额外的研究：a）分析血管平滑肌细胞和免疫细胞中IKca表达控制的分子机制，B）寻找靶向血管平滑肌细胞和免疫细胞中IKca表达的治疗药物，B ...更多信息 3.用血管紧张素Ⅱ和血小板源性生长因子（PDGF）刺激大鼠主动脉血管平滑肌细胞，分析BTEB 2和IKca表达与表型转化的关系，以及NO供体和超氧阴离子对IKca表达的影响。BTEB 2和IKca表达的增加被NO供体降低，并被超氧阴离子增强。在血管疾病的基础临床状态模型中寻找靶向IKca表达的治疗药物4. NFk-B激活剂与IKca启动子之间的关系，NFk-B激活剂是一种对氧化还原敏感的转录因子，和IKca在平滑肌和T淋巴细胞的表达进行了讨论与接受长期L-NAME管理的大鼠。此外，作为抑制IKca表达和NFkB活化的指标，分析了以下药物的功效：（1）咪唑/吡唑类药物、克霉唑、TRAM 34（均为选择性IKca抑制剂），（2）他汀类药物，和（3）NS 1619。尽管所有药物倾向于抑制IKca表达和NFkB活化，但未观察到显著差异。(4)低分子量肝素，具有抗血小板和抗炎特性，使用大鼠接受长期L-NAME管理的影响进行了研究。低分子量肝素抑制心血管重塑，发生与长期L-NAME管理，如冠状动脉周围纤维化和增加中膜平滑肌肥大。少

项目成果

The effect of Unoprostone on store operated Ca entry in human aortic smooth muscle cells.

乌诺前列酮对人主动脉平滑肌细胞中钙离子储存操作的影响。

• 发表时间: 2005
• 期刊: Akita J Med 32
• 作者: Akiko Watanabe;Hiroyuki Watanabe;Kyoichi Ono;Tkayoshi Ohba;Manabu Murakami;Hitoshi Hasegawa;Masahiro Sasaki;Toshihiko Iijima;Yoshitomi T;Ito H.
• 通讯作者: Ito H.

Essential role of the N-terminus of murine Orail in store-operated Ca^<2+>entry

小鼠 Orail N 末端在库操作 Ca^<2 > 进入中的重要作用

• 发表时间: 2007
• 期刊: Biochemical & Biophysical Research communications 356
• 作者: Takahashi;Y.;et. al.
• 通讯作者: et. al.

Low Molecular Weight Heparin Prevents Cardiovascular Remodeling Induced by the Long-Term Inhibition of Nitric Oxide Synthase with N-Nitro-L-Arginine Methyl Ester in Rat Hearts

• 发表时间: 2004-12
• 作者: H. Hasegawa;Takashi Saito;Yoshimasa Fujiwara;F. Kurokawa;T. Kosaka;Hiroyuki Watanabe;K. Iino;Masaru Ishida;T. Koyama;Kouichi Kawamura;H. Masuda;M. Miura;Hiroshi Ito