Published Online
on August 23, 2004

A more recent version of this article appeared on September 7, 2004

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Submitted on October 13, 2003
Revised on May 13, 2004
Accepted on May 19, 2004

Protective Effect of Propylthiouracil Independent of Its Hypothyroid Effect on Atherogenesis in Cholesterol-Fed Rabbits. PTEN Induction and Inhibition of Vascular Smooth Muscle Cell Proliferation and Migration

Wei-Jan Chen MD, PhD, Kwang-Huei Lin PhD, Ying-Ju Lai , Su-Hui Yang , and Jong-Hwei S. Pang PhD^*

From the First Cardiovascular Division, Chang Gung Memorial Hospital (W.-J.C., Y.-J.L., S.-H.Y.), and Department of Biochemistry (K.-H.L.) and Graduate Institute of Clinical Medical Sciences (J.-H.S.P.), Chang Gung University, Tao-Yuan, Taiwan.

^* To whom correspondence should be addressed. E-mail: jonghwei{at}mail.cgu.edu.tw.

Background--Propylthiouracil (PTU) is used to treat hyperthyroid patients by its hypothyroid effect. PTU also is found to have potent antioxidant and immunosuppressive effects. These findings suggest that PTU may play a role in the prevention of atherosclerosis.

Methods and Results--This study evaluates the effect of PTU on atherosclerotic change in rabbits fed a high-cholesterol diet. The pronounced atherosclerotic lesions in the aortas of rabbits fed a 2% cholesterol diet for 12 weeks were significantly attenuated by the concurrent addition of 0.1% PTU to the drinking water. However, exogenous supplementation of thyroid hormone in hypothyroid PTU-treated rabbits did not abrogate the protective effect of PTU on atherogenesis. Immunohistochemical analysis showed that PTU administration apparently reduced the intimal smooth muscle cell/macrophage ratio in the atherosclerotic plaques of rabbits fed a 2% cholesterol diet. In vitro, the addition of PTU to the medium of cultured rat vascular smooth muscle cells led to a dose-dependent inhibition of cell proliferation and migration. Furthermore, this study confirmed that PTU dose-dependently increased expression of PTEN, a tumor suppressor gene known to be involved in the coordinate inhibition of VSMC proliferation and migration.

Conclusions--This study demonstrated that PTU inhibited the development of atherosclerosis through a thyroid-independent mechanism that may be explained, at least in part, by the ability of PTU to inhibit vascular smooth muscle cell proliferation and migration. Furthermore, PTEN induction, via disruption of the phosphatidylinsitol 3-kinase-mediated pathway, plays a crucial role in mediating the inhibitory action on vascular smooth muscle cell proliferation and migration.

Key words: atherosclerosis • propylthiouracil • muscle, smooth, vascular • tumor suppressor proteins

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