Clarification of the role of apoptosis in the formation of vascular lesion and application of apoptosis-inducing factor to the treatment of restenosis after stent implantation.

阐明细胞凋亡在血管病变形成中的作用及凋亡诱导因子在支架植入后再狭窄治疗中的应用。

• 批准号: 17590742
• 负责人: ICHIKI Toshihiro
• 金额: $ 2.24万
• 依托单位: KYUSHU UNIVERCITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590742/
• 关键词: Mst1; Apoptosis; vascular smooth muscle cell; endothelial cell; TNFα; balloon injury model of rat carotid artery; siRNA; ICER; 頚動脈バルーン障害モデル; スタウロスポリン; 頸動脈バルーン傷害モデル

Mst1 is a serine/threonine kinase that is involved in the process of apoptosis. However, the role of Mstl in the blood vessel has not been reported to date. Stimulation of vascular smooth muscle cells (VSMCs) with staturosporine induced apoptosis as well as activation of Mstl. After balloon injury of rat carotid artery, the expression of Mstl was increased in the neointima. Overexpression of Mstl by an adenovirus vector in the injured rat carotid artery enhanced the number of TUNEL positive cells and reduced the extent of neointimal formation. We also found that tumor necrosis factor □ (TNF□) induced activation of Mstl in endothelial cells (ECs) through induction of reactive oxygen species. Knockdown of the Mstl expression by siRNA attenuated TNF□ -induced apoptosis of ECs.We next examined the role of inducible cAMP early repressor (ICER), a transcription repressor, of which expression is induced by cAMP. Beraprost, a PGI2 derivative, induced the expression of ICER in VSMCs in a dose-and time-dependent manner. Beraprost inhibited platelet-derived growth factor-induced growth of VSMCs. Knockdown of ICER expression by siRNA attenuated the beraprost-induced growth suppression, suggesting that beraprost-induced growth suppression is, at least in part, mediated by induction of ICER. Overexpression of ICER by an adenovirus vector induced the apoptosis of VSMCs and inhibited neointimal formation after balloon injury of rat carotid artery.These results suggest that it may be possible to inhibit growth of VSMCs by modulating the expression and/or activity of Mstl or ICER. These molcules may be applied to the treatment of vascular diseases such as atherosclerosis and in-stent restenosis.

mst 1是一种丝氨酸/苏氨酸激酶，参与细胞凋亡过程。然而，Mstl在血管中的作用至今尚未报道。用staturosporine刺激血管平滑肌细胞（VSMCs）诱导凋亡以及Mstl的激活。大鼠颈动脉球囊损伤后，新生内膜中Mstl表达增加。在大鼠颈动脉损伤后，腺病毒载体过表达Mstl可增加TUNEL阳性细胞的数量，减少新生内膜形成的程度。我们还发现，肿瘤坏死因子□（TNF□）通过诱导活性氧来诱导内皮细胞（EC）中Mstl的活化。通过siRNA敲低Mstl表达减弱了TNF□诱导的ECs凋亡。我们接下来研究了诱导型cAMP早期阻遏物（ICER）的作用，ICER是一种转录阻遏物，其表达由cAMP诱导。贝前列素，PGI 2衍生物，诱导ICER在VSMCs中的表达呈剂量和时间依赖性。贝前列素抑制血小板衍生生长因子诱导的VSMCs生长。通过siRNA敲减ICER表达减弱了贝前列素诱导的生长抑制，表明贝前列素诱导的生长抑制至少部分是由ICER诱导介导的。腺病毒载体介导ICER过表达可诱导大鼠颈动脉球囊损伤后VSMCs凋亡，抑制新生内膜的形成，提示可能通过调节Mstl或ICER的表达和/或活性来抑制VSMCs的生长。这些分子可用于治疗动脉粥样硬化和支架内再狭窄等血管疾病。

项目成果

Thyroid hormone inhibits vascular remodeling through suppression of cAMP response element binding protein activity

• DOI: 10.1161/01.atv.0000233358.87583.01
• 发表时间: 2006-09-01
• 期刊: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
• 影响因子: 8.7
• 作者: Fukuyama, Kae;Ichiki, Toshihiro;Sunagawa, Kenji
• 通讯作者: Sunagawa, Kenji

cAMP-response element-binding protein mediates tumor necrosis factor-a induced vascular cell adhesion molecule-1 expression in endothelial cells.

cAMP 反应元件结合蛋白介导肿瘤坏死因子 -a 诱导的血管细胞粘附分子 -1 在内皮细胞中的表达。

• 发表时间: 2006
• 期刊: Hypertension Research 29
• 作者: Ono H;Ichiki T;Ohtsubo H;Fukuyama K;Imayama I;Iino N;Masuda S;Hashiguchi Y;Takeshita A;Sunagawa K
• 通讯作者: Sunagawa K

cAMP-response element-binding protein mediates tumor necrosis factor-a induced vascular cell adhesion molecule-1 expression in endothelial cells

cAMP反应元件结合蛋白介导肿瘤坏死因子-a诱导内皮细胞中血管细胞粘附分子-1的表达

• 发表时间: 2006
• 期刊: Hypertension Research 29
• 作者: Fukuyama K;Ichiki T;Imayama I;Ohtsubo H;Ono H;Hashiguchi Y;Takeshita A;Sunagawa K.;Maruyama R;Yokoyama M;Ono H et al.
• 通讯作者: Ono H et al.

Critical role of Mstl in vascular remodeling after injury.

Mstl 在损伤后血管重塑中的关键作用。

• 发表时间: 2005
• 期刊: Arteriosclerosis Thrombosis and Vascular Biology. 25
• 作者: Ono H;Ichiki T;Ohtsubo H;Fukuyama K;Imayama I;Hashiguchi Y;Sadoshima J;Sunagawa K
• 通讯作者: Sunagawa K

Inducible cAMP early repressor inhibits growth of vascular smooth muscle cell

• DOI: 10.1161/atvbaha.107.145011
• 发表时间: 2007-07-01
• 期刊: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
• 影响因子: 8.7
• 作者: Ohtsubo, Hideki;Ichiki, Toshihiro;Sunagawa, Kenji
• 通讯作者: Sunagawa, Kenji