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，多种危险因素，例如肥胖，葡萄糖肠，血脂异常和高血压协同，并进一步增加冠状动脉疾病的风险。最近的研究表明，脂肪组织是产生各种脂肪细胞因子的内分泌器官。在代谢综合征下动脉粥样硬化的进展过程中，暗示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的分子机制知之甚少。在先前的研究中，我们已经证明了锌指转录，因子，类似Kruppel的因子5（KLF5）在响应外部刺激的心血管重塑中起着至关重要的作用。在本研究中，我们分析了心血管系统和脂肪组织中包含KLF5的转录因子网络的功能。我们还分析了脂肪细胞因子对血管中KLF5的影响。我们发现KLF5在控制脂肪细胞分化的转录因子网络中起着核心作用。 KLF5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，KLF5与视黄酸受体相互作用。 RAR在KLF5依赖t的转录调控中充当反式激活器。基于这一事实，我们发现合成性类维生素AM80抑制了KLF5功能。此外，我们发现脂联素抑制血管紧张素II在血管平滑肌细胞中诱导的KLF5表达，这意味着脂肪细胞因子可能直接影响血管细胞功能。我们还基于KLF5和PPARγ之间的相互作用建立了高通量药物筛查系统。

项目成果

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

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

Synthetic retinoid Am80 reduces scavenger receptor expression and atherosclerosis in mice by inhibiting IL-6

• DOI: 10.1161/01.atv.0000214296.94849.1c
• 发表时间: 2006-05-01
• 期刊: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
• 影响因子: 8.7
• 作者: Takeda, N;Manabe, I;Nagai, R
• 通讯作者: Nagai, R

Significance of the transcription factor KLF5 in cardiovascular remodeling

• DOI: 10.1111/j.1538-7836.2005.01366.x
• 发表时间: 2005-08-01
• 期刊: JOURNAL OF THROMBOSIS AND HAEMOSTASIS
• 影响因子: 10.4
• 作者: Nagai, R;Suzuki, T;Manabe, I
• 通讯作者: Manabe, I

Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells.

抵抗素和脂联素对血管内皮细胞的直接相互作用。

• 发表时间: 2004
• 期刊: Biochemical Biophysical Research Communication 314・2
• 作者: Shishido T;Nozaki N;Miyamoto T;Takahashi H;Arimoto T;Takeishi Y;Kubota I;Takeda N;Takeishi Y;Kawanami D
• 通讯作者: Kawanami D