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.在本研究中，ca激活的K通道（IKca）的表达和功能的抑制参与血管炎症和随后的血管重塑形成，如细胞增殖和去分化，被研究作为血管病变形成的治疗靶点。血管平滑肌细胞和免疫系统细胞中IKca表达调控的分子机制分析。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血管病变的形成与IKca在血管和免疫细胞中的表达改变之间的关系，同时分析IKca作为新的治疗靶点的可能性，我们陆续进行了以下进一步的研究：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)寻找靶向血管疾病临床状态模型中IKca表达的治疗药物。采用外植体法获得大鼠主动脉血管平滑肌细胞，在血管紧张素II和PDGF刺激下培养，分析BTEB2表达与IKca在表型转化为增殖形式时的关系，以及NO供体和超氧阴离子对IKca表达的影响。BTEB2和IKca表达的增加在一氧化氮供体中降低，在超氧阴离子中增强。寻找一种靶向血管疾病基础临床状态模型中IKca表达的治疗药物4。NFk-B激活因子是一种对氧化还原敏感的转录因子，对NO减少导致的超氧阴离子产生增加敏感，在IKca启动子上有相应的位点，我们讨论了长期服用L-NAME的大鼠平滑肌和t淋巴细胞中IKca表达的关系。此外，作为IKca表达抑制和NFkB活化的指标，分析了以下几种药物的疗效：(1)咪唑/吡唑类药物、克霉唑、TRAM34（均为选择性IKca抑制剂）、(2)他汀类药物、(3)NS1619。虽然所有药物都倾向于抑制IKca的表达和NFkB的激活，但没有观察到显著差异。(4)低分子肝素具有抗血小板和抗炎作用，通过大鼠长期给予L-NAME研究其作用。低分子肝素抑制长时间使用L-NAME时发生的心血管重构，如冠状动脉周围纤维化和内侧平滑肌肥大增加。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