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Prepublished online as a Blood First Edition Paper on July 25, 2002; DOI 10.1182/blood-2002-03-0945.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4011-4018
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
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
From the First Department of Internal Medicine, Nagoya
University School of Medicine, Aichi Blood Disease Research Foundation,
Department of Medical Technology, Nagoya University School of Health
Sciences, and Nagoya National Hospital, Nagoya, Japan;
Department of Basic Gerontology, National Institute for Longevity
Sciences, Obu, Japan; and Department of Vascular Biology
(VB-3), The Scripps Research Institute, La Jolla, CA.
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 hours of restraint stress to mice caused a
substantial 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 was 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 pretreatment 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 of
stress-associated thrombosis in older and obese subjects and that
TNF- may be involved.
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