| Budget Amount *help |
¥3,950,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Psychological stress(i.e. restraint stress) led to a dramatic induction of plasma plasminogen activator inhibitor-1(PAI-1) antigen and of tissue PAI-1 mRNA with maximum induction in adipose tissues. In situ hybridization analysis of the stressed mice revealed that strong signals for PM-1 mRNA were localizad to hepatocytes, renal tubular epithelial cells, adrenomedullar chromaffin cells, neural cells in the paraaortic sympathetic ganglion, vascular smooth muscle cells, and adipocytes, but not to endothelial cells. These observations indicate that the stress induces the PAI-1 gene expression in a tissue-specific and cell type-specific manner. The induction of PAI-1 mRNA by restraint stress was greater than that observed for heat shock protein, a typical stress protein, suggesting that PAI-1 is one of the most highly induced stress proteins. Importantly, the magnitude of induction of PAI-1 mRNA by stress increased markedly with age, and this increase in PAI-1 correlated with tissue thromb
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osis in the older stressed mice. Moreover, much less tissue thrombosis was induced by restraint stress in young and aged PAI-1 deficient mire compared with age-matched wild-type mice. These results suggest that the large induction of PAI-1 by stress increases the risk for thrombosis in the older populations, and that the adipose tissue may be involved.
Meanwhile, we investigated PAI-1 expression in a mouse model of myocardial infarction (MI) by coronary ligation, in which the progression of left ventricular remodeling was confirmed by echocardiography. Histological examination showed that interstitial and perivascular fibrosis progressed in the post MI(PMI)heart at 4 weeks after the procedure. We observed the dramatic induction of cardiac PAI-1 mRNA and PAI-1 antigen in plasma in the PMI mice, as compared with the sham-operated (Sham) mice. In situ hybridization analysis demonstrated that strong signals for PAI-1 mRNA were localized to cardiomyocytes in the boarder of infarct area and around fibrous lesions, and to perivascular mononuclear cells, which seemed to be mast cells, only in hearts of the PMI mice. Importantly, less development of cardiac fibrosis after MI was observed in mice deficient in PAI-1 as compared to wild-type mice. These observations suggest that cardiomyocytes and mast cells contribute to the increased PAI-1 expression, resulting in the development of interstitial and perivascular fibrosis in the PMI heart, and that the regional induction of cytokines may be involved in this process Less
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