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物-1(PAI-1)抗原和脂肪组织PAI-1mRNA的显著诱导。应激小鼠的原位杂交分析表明，PM-1mRNA的强信号定位于肝细胞、肾小管上皮细胞、肾上腺髓质嗜铬细胞、腹主动脉交感神经节神经细胞、血管平滑肌细胞和脂肪细胞，而不定位于内皮细胞。这些观察表明，应激以组织特异性和细胞类型特异性的方式诱导PAI-1基因的表达。束缚应激对PAI-1mRNA的诱导作用强于典型的应激蛋白热休克蛋白，提示PAI-1是诱导作用最强的应激蛋白之一。重要的是，应激诱导的PAI-1mRNA的大小随着年龄的增长而显著增加，并且这种增加与组织血栓…相关。年龄越大的应激小鼠越容易中毒。此外，与年龄匹配的野生型小鼠相比，年轻和老年PAI-1缺陷小鼠的束缚应激导致的组织血栓形成要少得多。这些结果表明，在老年人群中，PAI-1的大量诱导增加了血栓形成的风险，脂肪组织可能也受到了影响。同时，我们研究了PAI-1在冠状动脉结扎心肌梗死(MI)小鼠模型中的表达，在该模型中，超声心动图证实了左室重构的进展。组织学检查显示，术后4周心肌梗死后(PMI)心脏间质和血管周围纤维化进展。我们观察到，与假手术(Sham)组相比，PMI组小鼠血浆中心脏PAI-1mRNA和PAI-1抗原的表达显著增加。原位杂交分析显示，PAI-1mRNA的强信号定位于梗死区边缘和纤维性病变周围的心肌细胞，以及血管周围的单个核细胞，似乎是肥大细胞，仅在PMI小鼠的心脏中有表达。重要的是，与野生型小鼠相比，PAI-1缺陷小鼠在心肌梗死后较少发展成心肌纤维化。这些观察表明，心肌细胞和肥大细胞参与了PAI-1表达的增加，从而导致了PMI心脏间质和血管周围纤维化的发展，而局部细胞因子的诱导可能较少参与这一过程

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