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Prepublished online as a Blood First Edition Paper on July 25, 2002; DOI 10.1182/blood-2002-03-0945.
Submitted April 4, 2002
Accepted July 11, 2002
Aging and obesity augment the stress-induced expression of tissue factor gene in the mouse
Koji Yamamoto*, Takayoshi Shimokawa, Hong Yi, Ken-ichi Isobe, Tetsuhito Kojima, David J Loskutoff, and Hidehiko Saito
First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya University School of Medicine, Nagoya, Aichi, Japan; Aichi Blood Disease Research Foundation, Nagoya, Aichi, Japan
First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya University School of Medicine, Nagoya, Aichi, Japan
Department of Basic Gerontology, National Institute for Longevity Sciences, Obu, Aichi, Japan
Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Aichi, Japan
Department of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA
Nagoya National Hospital, Nagoya, Aichi, Japan
* Corresponding author; email: kojiy{at}tsuru.med.nagoya-u.ac.jp.
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 a procoagulant gene, tissue factor (TF), in a mouse model of restraint stress. Twenty hour-restraint stress to mice caused a significant induction of TF mRNA in several tissues. Importantly, the magnitude of induction of TF mRNA by restraint stress was larger in aged mice compared with young mice. In situ hybridization analysis of the stressed aged mice revealed that strong signals for TF mRNA were localized to renal epithelial cells, smooth muscle cells, adventitial cells, and adipocytes, but not to vascular endothelial cells. These observations suggest that restraint stress induces the TF expression in a tissue-specific and cell type-specific manner. Genetically obese mice were also hyperresponsive to restraint stress in the induction of TF gene, especially in their livers and adipose tissues. Stress-induced microthrombi formation were pronounced in renal glomeruli and within the vasculature in adipose tissues of aged mice. Tumor necrosis factor- (TNF-) antigen in plasma was elevated by stress, in aged mice and obese mice, and pre-treatment of mice with anti-TNF- antibody partially attenuated the stress-mediated induction of TF gene in adipose tissues in these mice. These results suggest that the induction of TF gene may increase the risk for stress-associated thrombosis in older and obese subjects and that TNF- may be involved.
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