Analysis and regulation of aberrant expression of sties-responsive prothrombotic genes in a model of myocardial and cerebral infarction

心理应激（即束缚应激）导致血浆纤溶酶原激活物抑制剂-1（派-1）抗原和组织派-1 mRNA的显著诱导，其中脂肪组织中的诱导最大。原位杂交结果显示，PM-1 mRNA主要表达于肝细胞、肾小管上皮细胞、肾上腺髓质嗜铬细胞、主动脉旁交感神经节神经细胞、血管平滑肌细胞和脂肪细胞，而不表达于内皮细胞。这些观察结果表明，压力诱导派-1基因表达的组织特异性和细胞类型特异性的方式。束缚应激对派-1 mRNA的诱导作用大于热休克蛋白（一种典型的应激蛋白），表明派-1是诱导作用最强的应激蛋白之一。更重要的是，压力诱导派-1 mRNA表达的幅度随着年龄的增长而显著增加，派-1的这种增加与组织血栓形成有关。 ...更多信息 老年应激小鼠的疾病。此外，与年龄匹配的野生型小鼠相比，年轻和老年派-1缺陷小鼠的束缚应激诱导的组织血栓形成要少得多。这些结果表明，大量诱导派-1的压力增加血栓形成的风险，在老年人中，脂肪组织可能参与其中。同时，我们研究了派-1的表达在小鼠模型的心肌梗死（MI）的冠状动脉结扎，其中左心室重构的进展证实了超声心动图。术后4周组织学检查显示心肌梗死后（PMI）心脏的间质和血管周围纤维化进展。与假手术组相比，PMI组小鼠心脏派-1 mRNA和血浆中派-1抗原显著增加。原位杂交结果显示，派-1 mRNA的强信号主要分布于心肌梗死区边缘和纤维病变周围的心肌细胞，而血管周围的单个核细胞（肥大细胞）仅分布于PMI小鼠的心脏。重要的是，与野生型小鼠相比，在派-1缺陷的小鼠中观察到MI后心脏纤维化的发展较少。这些观察结果表明，心肌细胞和肥大细胞有助于派-1表达的增加，导致PMI心脏中间质和血管周围纤维化的发展，并且细胞因子的区域诱导可能参与了这一过程。

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 … More 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