Development of atherosclerosis in osteopontin transgenic mice |
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Authors: | Chiba Satoru Okamoto Hiroshi Kon Shigeyuki Kimura Chiemi Murakami Masaaki Inobe Manabu Matsui Yutaka Sugawara Takeshi Shimizu Toshihiro Uede Toshimitsu Kitabatake Akira |
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Institution: | (1) Department of Cardiovascular Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan Tel. +81-11-716-1161 ext. 6973; Fax +81-11-706-7874 e-mail: okamotoh@hucc.hokudai,ac.jp, JP;(2) Section of Immunopathogenesis, Institute of Immunological Science, Hokkaido University, Sapporo, Japan, JP |
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Abstract: | Osteopontin (OPN), a noncollagenous adhesive protein, may possibly be implicated in atherosclerosis, in which macrophages
and activated T lymphocytes could have higher OPN levels within the atherosclerotic plaques. However, it is not known whether
a higher OPN level is a cause or a result of atherosclerosis or whether it has a promoting or inhibitory effect on atherosclerosis.
To clarify the role of OPN in atherosclerosis, we developed a transgenic mouse (OPN-TG) in which the exogenous OPN gene was
designed to be expressed by hematopoietic cells, expressing OPN, which carried the immunoglobulin enhancer (Eμ)/SV40 promoter.
In OPN-TG, the expression of exogenously transfected OPN RNA was found in lymphoid organs, such as the thymus and spleen,
and the kidney. In the present study, OPN-TG mice were assigned into two groups, an atherogenic diet group (15% fat, 1.25%
cholesterol) for 3 months or a standard diet group (4% fat), and both groups were compared with wild-type C57BL/6 mice to
investigate the relationship between osteopontin and the atherosclerotic lesion. In wild-type mice, OPN mRNA was detected
in kidney, but not in lymphoid tissues. In both OPN-TG and wild-type mice fed with control diets, atherosclerotic lesions
were not found in the aortic sinus or the thoracic and abdominal aorta. In both OPN-TG and wild-type mice fed with atherogenic
diets, a high incidence of atherosclerotic lesions was noted in the aortic sinus. The atherosclerotic lesions were significantly
larger in OPN-TG as compared with those in control littermate mice (size: 33.8% ± 23.4% vs 10.9% ± 20.4%, respectively, P < 0.05). Activated foamy macrophages within atherosclerotic plaque in OPN-TG expressed a considerably larger amount of OPN
compared with such macrophages in control mice. The OPN protein detected in the atherosclerotic lesions was not due to the
deposition of serum OPN, but mainly due to in situ production by the infiltrating macrophages. Thus, these results suggest
that OPN is atherogenic and that macrophages expressing OPN can be easily activated and thus promote atheromatous lesions
if a high fat diet is consumed.
Received: May 15, 2001 / Accepted: September 22, 2001 |
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Keywords: | Atherosclerosis Osteopontin Transgenic mouse Macrophage |
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