Role of redox-sensitive transcription factor in the progression of atherosclerosis Possible application to gene therapy.

氧化还原敏感转录因子在动脉粥样硬化进展中的作用可能应用于基因治疗。

• 批准号: 14570673
• 负责人: ICHIKI Toshihiro
• 金额: $ 2.24万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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-14570673/
• 关键词: Reactive oxygen species; Transcription factors; mitogen activated protein kinase; epidermal growth factor receptor; transactivation; cAMP response element binding protein

The aim of the present study is to identify redox-sensitive transcription factors and to analyze their role in the blood vessel. Angiotensin II that induces production of reactive oxygen species activated cAMP response element binding protein (CREB), a 43KDa nuclear transcription factor, in vascular smooth muscle cells. Hydrogen peroxide (1-1202) also activated CREB, (VSMC). H_2O_2 transiently activated CREB after 15 minutes of stimulation in ERK-and p38MAPK-dependent manner. An inhibitor for epidermal growth factor receptor (EGF-R) also suppressed H_2O_2-induced activation of CREB, suggesting that transactivation of EGF-R plays an important role in the activation of CREB. Indeed, H_2O_2 induced tyrosine phosphorylation of EGF-R. Activation of CREB by All was inhibited by N-acetylcysteine, a potent antioxidant, suggesting a critical role of reactive oxygen species in All signaling. These data suggest that CREB is a redox-sensitive transcription factor. Overexpression of dominant negative CREB by an adenovirus vector decreased Bcl-2 expression in VSMC and resulted in the induction of apoptosis. Infection of adenovirus expressing dominant negative CREB suppressed neointimal formation after balloon injury of rat carotid artery with an increase in TUNEL positive cells. These data suggest that CREB is an important redox-sensitive transcription factor that mediates survival and proliferation of VSMC. And it was suggested that CREB may be a novel therapeutic target to treat vascular diseases.

本研究的目的是识别氧化还原敏感的转录因子，并分析它们在血管中的作用。血管紧张素II可诱导血管平滑肌细胞产生43 KDa的核转录因子--活性氧激活的cAMP反应元件结合蛋白(CREB)。过氧化氢(1-1202)也激活CREB(VSMC)。H_2O_2以ERK和p38MAPK依赖的方式在刺激15分钟后瞬间激活CREB。表皮生长因子受体(EGF-R)的抑制剂也能抑制H_2O_2诱导的CREB的激活，提示EGF-R的反式激活在CREB的激活中起重要作用。的确，H_2O_2诱导EGF-R酪氨酸磷酸化。有效的抗氧化剂N-乙酰半胱氨酸可抑制ALL激活CREB，提示活性氧在ALL信号转导中起关键作用。这些数据表明CREB是一个氧化还原敏感的转录因子。腺病毒载体过表达显性负性CREB可降低VSMC中Bcl2的表达，从而诱导细胞凋亡。表达显性阴性CREB的腺病毒感染可抑制大鼠颈动脉球囊损伤后新生内膜的形成，并使TUNEL阳性细胞增多。这些数据表明，CREB是一种重要的氧化还原敏感转录因子，参与VSMC的存活和增殖。提示CREB可能成为治疗血管疾病的新靶点。

项目成果

Funakoshi Y, Ichiki T et al.: "Critical role of cAMP response element-binding protein (CREB) for angiotensin II-induced hypertrophy of vascular smooth muscle cells."Hypertension. 277. 18710-18717 (2002)

Funakoshi Y、Ichiki T 等人：“cAMP 反应元件结合蛋白 (CREB) 对于血管紧张素 II 诱导的血管平滑肌细胞肥大的关键作用。”高血压。

Funakoshi Y., Ichiki T et al.: "Critical role of cAMP response element-binding protein (CREB) for angiotensin II-induced hypertrophy of vascular smooth muscle cells."Journal of Biological Chemistry. 277. 18710-18717 (2002)

Funakoshi Y.、Ichiki T 等人：“cAMP 反应元件结合蛋白 (CREB) 对于血管紧张素 II 诱导的血管平滑肌细胞肥大的关键作用。”生物化学杂志。

Funakoshi Y., Ichiki T et al.: "Critical role of cAMP response element-binding protein (CREB) for angiotensin II-induced hypertrophy of vascular smooth muscle cells"Journal of Biological Chemistry. 277. 18710-18717 (2002)

Funakoshi Y.、Ichiki T 等人：“cAMP 反应元件结合蛋白 (CREB) 对于血管紧张素 II 诱导的血管平滑肌细胞肥大的关键作用”生物化学杂志。

Ichiki T et al.: "A.cAMP response element binding protein mediates reactive oxygen species-induced c-fos expression."Hypertension. 42. 177-183 (2003)

Ichiki T 等人：“A.cAMP 反应元件结合蛋白介导活性氧诱导的 c-fos 表达。”高血压。

Ichiki T, et al.: "A. cAMP response element binding protein mediates reactive oxygen species-induced c-fos expression."Hypertension. 42. 177-183 (2003)

Ichiki T 等人：“A. cAMP 反应元件结合蛋白介导活性氧诱导的 c-fos 表达。”高血压。