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

点击翻译按钮获取中文摘要

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.