| Budget Amount *help |
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2004: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2003: ¥8,200,000 (Direct Cost: ¥8,200,000)
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| Research Abstract |
Myocardial infarction frequently occurs in the morning, a phenomena in part resulting from the down regulation of fibrinolytic activity. Plasminogen activator inhibitor-1(PAI-1) is a key factor behind fibrinolytic activity, and its gene expression shows circadian change in the mouse heart and liver. Hypercholesterolaemia has been associated with impaired fibrinolysis due to enhanced PAI-1, which has also been implicated in atherosclerosis. The aim of this study was to decipher whether the Pai-1 gene is still expressed daily with hypercholesterolaemia. We found that a diet containing 1 % cholesterol (hypercholesterolaemia) strongly enhanced daily expression of the Pai-1 gene in the mouse liver but not the heart. Hypercholesterolaemia did not affect the daily expression of clock genes (Per2 and Bmal1) and clock-controlled genes (Dbp and E4bp4) in the liver ; however daily expression of Pai-1 promoter regulating factor genes such as Nr4a1 and TNF-alpha but not the VLDL receptor, was up-re
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gulated. Daily restricted feeding for 4 hrs during the day reset the gene expression of Per2, Pai-1, Nr4a1, and TNF-alpha. Lesion of the suprachiasmatic nucleus, location of the main clock system, led to loss of Per2 and Pai-1 daily expression. The present experiment demonstrates that hypercholesterolaemia enhanced daily expression of Pai-1, TNF-alpha, and Nr4a1 gene expression in the mouse liver without affecting clock and clock-controlled genes. Thus, the risk or high frequency of acute atherothrombotic events in the morning still seems to be factor that may be augmented under hypercholesterolaemia conditions.
Mouse Pai-1 shows a daily rhythm in vivo, and its transcription is seems to be controlled not only by clock genes but also by humoral factors such as insulin and triglyceride. Thus, we investigated daily clock genes and mPai-1 mRNA expression in the liver of db/db mice exhibiting high levels of glucose, insulin, and triglyceride. db/db mice showed attenuated locomotor activity rhythms. The rhythmic expression of mPer2 mRNA was severely dampened, and the phase of mBmal1 oscillation was advanced in the db/db mouse liver, while mPai-1 mRNA was highly and constitutively expressed. Night-time restricted feeding led to a recovery from not only the dampened locomotor activity, but also from the dampened mPer2 and advanced mBmal1 mRNA rhythms. mPai-1 mRNA expression in db/db mice was reduced far below normal levels. We demonstrated that insulin-independent diabetes impaired the oscillation of the peripheral oscillator. Night-time restricted feeding rather than pioglitazone injection led to a recovery from the dampened locomotor activity and altered oscillation of the peripheral clock and mPai-1 mRNA rhythm. Thus, we conclude that scheduled restricted food-intake may be a useful form of treatment for diabetes. Less
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