Molecular mechanisms of thrombosis in mouse model induced by age and stress

高凝状态和血栓形成倾向常由各种应激因素引起。临床上，老年人和肥胖患者更容易发生与应激相关的血栓性疾病，但其潜在机制尚不清楚。我们研究了束缚应激小鼠模型中纤溶酶原激活物抑制剂-1（派-1）和组织因子（TF）的表达。束缚应激20 h可诱导小鼠多个组织中派-1和TF mRNA的表达。重要的是，与年轻小鼠相比，老年小鼠中束缚应激诱导派-1和TF mRNA的幅度更大。原位杂交分析显示，派-1 mRNA和TF mRNA的强信号定位于肾上皮细胞、平滑肌细胞和脂肪细胞。这些观察结果表明，束缚应激诱导派-1和TF的表达在组织特异性和细胞类型特异性的方式。遗传性肥胖小鼠对束缚应激也有高反应性，派-1基因和TF基因在其肝脏和脂肪组织中也有表达。应激诱导的微血栓形成在老年小鼠的肾小球和脂肪组织中的血管系统内明显。老年小鼠和肥胖小鼠血浆中肿瘤坏死因子-α（TNF-α）抗原在应激后升高，抗TNF-α抗体预处理可部分减弱应激诱导的脂肪组织TF基因表达。这些结果表明，派-1和TF基因的诱导可能会增加老年人和肥胖受试者的应激相关血栓形成的风险，TNF-α可能参与其中。

Hypercoagulability and thrombotic tendency are frequently induced by a variety of stressors. Clinically, aged subjects and obese patients are more susceptible to thrombotic diseases associated with stress, but the underlying mechanisms are unknown. We investigated the expression of plasminogen activator inhibitor-1(PAI-1) and tissue factor(TF), in a mouse model of restraint stress. Twenty hours of restraint stress to mice caused inductions of PAI-1 and TF mRNAs in several tissues. Importantly, the magnitude of inductions of PAI-1 and TF mRNAs by restraint stress were larger in aged mice compared with young mice. In situ hybridization analysis of the stressed aged mice revealed that strong signals for PAI-1 mRNA as well as TF mRNA were localized to renal epithelial cells, smooth muscle cells, and adipocytes. These observations suggest that restraint stress induces the PAI-1 and TF expressions in a tissue-specific and cell type-specific manner. Genetically obese mice also hyperresponsive to restraint stress in the induction of PAI-1 gena and TF gene, especially in their livers and adipose tissues. Stress-induced microthrombi formation was pronounced in renal glomeruli and within the vasculature in adipose tissues of aged mice. Tumor necrosis factor-α(TNF-α) antigen in plasma was elevated by stress in aged mice and obese mice, and pretreatment of mice with anti-TNF-α antibody partially attenuated the stressmediated induction of TF gene in adipose tissues in these mice. These results suggest that the induction of PAI-1 and TF genes may increase the risk of stress-associated thrombosis in older and obese subjects and that TNF-α may be involved.