Increased Expression of Plasminogen Activator Inhibitor-1 with Fibrin Deposition in a Murine Model of Aging,

Kyosuke Takeshita; Koji Yamamoto; Masafumi Ito; Takahisa Kondo; Tadashi Matsushita; Makoto Hirai; Tetsuhito Kojima; Masahiko Nishimura; Yoichi Nabeshima; David J. Loskutoff; Hidehiko Saito; Toyoaki Murohara

doi:10.1055/s-2002-36699

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Semin Thromb Hemost 2002; 28(6): 545-554
DOI: 10.1055/s-2002-36699

Increased Expression of Plasminogen Activator Inhibitor-1 with Fibrin Deposition in a Murine Model of Aging, "Klotho" Mouse

Kyosuke Takeshita¹ , Koji Yamamoto¹ , Masafumi Ito² , Takahisa Kondo¹ , Tadashi Matsushita¹ , Makoto Hirai¹ , Tetsuhito Kojima³ , Masahiko Nishimura⁴ , Yoichi Nabeshima⁵ , David J. Loskutoff⁶ , Hidehiko Saito⁷ , Toyoaki Murohara¹

¹First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya
²Department of Pathology, Nagoya University Hospital, Nagoya
³Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya
⁴Institute for Laboratory Animal Research, Nagoya University School of Medicine, Nagoya
⁵Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan
⁶Department of Vascular Biology (VB-3), The Scripps Research Institute, La Jolla, California
⁷Nagoya National Hospital, Nagoya, Japan

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Publication Date:
21 January 2003 (online)

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ABSTRACT

Although aging accompanies specific pathological changes, including thrombosis and organ sclerosis, the underlying mechanisms of these processes remain to be elucidated. In the present study, we analyzed the gene expression of plasminogen activator inhibitor-1 (PAI-1), a key molecule in the development of thrombosis, in a murine model of aging, klotho mutant (kl/kl) mice. Active PAI-1 antigen in plasma and PAI-1 mRNA in several tissues were strikingly elevated in kl/kl mice as compared with wild-type mice. This increased PAI-1 expression was age dependent and linked to the development of ectopic calcification and glomerular fibrin deposition in the kidneys. In situ hybridization analysis of kl/kl mice demonstrated that strong signals for PAI-1 mRNA were localized in renal tubular epithelial cells, cardiomyocytes, adrenal medullar cells, and smooth muscle and endothelial cells in Mönckeberg's arteriosclerotic vessels. Renal glomerular fibrin deposition, as evaluated immunohistochemically, was occasionally observed only in kl/kl mice, and the number of fibrin-positive glomeruli increased as the kl/kl mice aged. These observations suggest that in the process of aging the PAI-1 gene expression is increased, contributing to the development of thrombosis.

KEYWORD

Thrombosis - fibrinolysis - proteolysis - gene expression - sclerosis

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