| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
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.
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