Transcriptional regulation and signaling in the interaction between vascular cells and adipocytes in metabolic syndrome

代谢综合征中血管细胞和脂肪细胞相互作用的转录调控和信号传导

• 批准号: 16590661
• 负责人: MANABE Ichiro
• 金额: $ 2.18万
• 依托单位: The University of Tokyo
• 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 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590661/
• 关键词: atherosclerosis; smooth muscle cell; transcription factor; metabolic syndrome; siRNA; tissue remodeling; adipocyte; obesity; メタボリック症候群

In metabolic syndrome, multiple risk factors, such as obesity, glucose intolerance, dyslipidemia and hypertension synergize and further increase the risk of coronary heart diseases. Recent studies have revealed that the adipose tissue functions as an endocrine organ that produces various adipocytokines. During progression of atherosclerosis under metabolic syndrome, it is implied that adipocytokines might directly affect cell function in the blood vessel. However, the molecular mechanism by which adipocytokines affect blood vessel functions and lead to atherogenesis is poorly understood. In the previous studies, we have demonstrated that a zinc finger transcription, factor, Kruppel-like factor 5 (KLF5) plays an essential role in cardiovascular remodeling in response to external stimuli. In the present study, we analyzed functions of the transcription factor network containing KLF5 in the cardiovascular system and adipose tissue. We also analyzed the effect of adipocytokines on KLF5 in the blood vessel. We found that KLF5 plays a central role in the transcription factor network that controls adipocyte differentiation. KLF5 interacts with C/EBP and regulates PPARγ_2. In vascular smooth muscle cells, on the other hand, KLF5 interacts with retinoic acid receptor, RAR. RAR functions as a transactivator in KLF5-dependet transcriptional regulation. Based on this fact, we found that a synthetic retinoid Am80 inhibits KLF5 function. Moreover, we found that adiponectin inhibits KLF5 expression induced by angiotensin II in vascular smooth muscle cells, implying that adipocytokines may directly affect vascular cell functions. We also established a high-throughput drug screening system based on the interaction between KLF5 and PPARγ.

在代谢综合征中，肥胖、糖耐量异常、血脂异常和高血压等多种危险因素协同作用，进一步增加冠心病的风险。最近的研究表明，脂肪组织作为一种内分泌器官，产生各种脂肪细胞因子。在代谢综合征下动脉粥样硬化的进展过程中，脂肪细胞因子可能直接影响血管中的细胞功能。然而，脂肪细胞因子影响血管功能并导致动脉粥样硬化形成的分子机制知之甚少。在以前的研究中，我们已经证明，锌指转录因子，Kruppel样因子5（KLF 5）在心血管重构中起着至关重要的作用，以响应外部刺激。在本研究中，我们分析了包含KLF 5的转录因子网络在心血管系统和脂肪组织中的功能。我们还分析了脂肪细胞因子对血管中KLF 5的影响。我们发现KLF 5在控制脂肪细胞分化的转录因子网络中起着核心作用。KLF 5与C/EBP相互作用并调节PPARγ_2。另一方面，在血管平滑肌细胞中，KLF 5与视黄酸受体RAR相互作用。RAR在KLF 5依赖的转录调控中作为反式激活因子发挥作用。基于这一事实，我们发现合成的维甲酸Am 80抑制KLF 5功能。此外，我们发现脂联素抑制血管紧张素II诱导的血管平滑肌细胞KLF 5的表达，这意味着脂肪细胞因子可能直接影响血管细胞功能。我们还建立了一个基于KLF 5与PPARγ相互作用的高通量药物筛选系统。

项目成果

Vasorin, a transforming growth factor beta-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo

Vasorin 是一种在血管平滑肌细胞中表达的转化生长因子 β 结合蛋白，可调节动脉对体内损伤的反应

• 发表时间: 2004
• 期刊: Proc Natl Acad Sci U S A 101
• 作者: Ikeda Y;et al.
• 通讯作者: et al.

Vasorin, a transforming growth factor β-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo

• DOI: 10.1073/pnas.0404117101
• 发表时间: 2004-07-20
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Ikeda, Y;Imai, Y;Kitamura, T
• 通讯作者: Kitamura, T

Synthetic retinoid Am80 suppresses smooth muscle phenotypic modulation and in-stent neointima formation by inhibiting KLF5

• DOI: 10.1161/01.res.0000190613.22565.13
• 发表时间: 2005-11-25
• 期刊: CIRCULATION RESEARCH
• 影响因子: 20.1
• 作者: Fujiu, K;Manabe, I;Nagai, R
• 通讯作者: Nagai, R

Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine-endothelial cell interactions

• DOI: 10.1016/j.bbrc.2003.12.104
• 发表时间: 2004-02-06
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Kawanami, D;Maemura, K;Nagai, R
• 通讯作者: Nagai, R

C-reactive protein induces VCAM-1 gene expression through NF-kappaB activation in vascular endothelial cells.

• 发表时间: 2006
• 期刊: Atherosclerosis
• 影响因子: 5.3
• 作者: Daiji Kawanami;K. Maemura;Norihiko Takeda;T. Harada;T. Nojiri;Tetsuya Saito;I. Manabe;Y. Imai;R. Nagai