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
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
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DOI：
10.1161/01.cir.0000140764.15398.f3
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发表时间：
2004-09-01
期刊：
影响因子：
37.8
通讯作者：
Pang, JHS
中科院分区：
文献类型：
--
作者：
Chen, WJ;Lin, KH;Pang, JHS
背景-丙基硫氧嘧啶（PTU）通过其甲状腺功能减退作用来治疗甲状腺功能亢进患者。 PTU 还被发现具有有效的抗氧化和免疫抑制作用。这些发现表明PTU可能在预防动脉粥样硬化中发挥作用。方法和结果-本研究评估了PTU对高胆固醇饮食兔子的动脉粥样硬化变化的影响。饲喂 2% 胆固醇饮食 12 周的兔子主动脉中明显的动脉粥样硬化病变，在饮用水中同时添加 0.1% PTU 后显着减轻。然而，在甲状腺功能减退症PTU治疗的兔子中外源性补充甲状腺激素并没有消除PTU对动脉粥样硬化形成的保护作用。免疫组织化学分析表明，给予2%胆固醇饮食的兔子动脉粥样硬化斑块中，PTU给药明显降低了内膜平滑肌细胞/巨噬细胞的比例。在体外，向培养的大鼠血管平滑肌细胞的培养基中添加 PTU 会导致细胞增殖和迁移的剂量依赖性抑制。此外，这项研究证实，PTU 剂量依赖性地增加 PTEN 的表达，PTEN 是一种肿瘤抑制基因，已知参与协调抑制 VSMC 增殖和迁移。结论 - 这项研究表明，PTU 通过甲状腺独立机制抑制动脉粥样硬化的发展，该机制至少部分可以通过 PTU 抑制血管平滑肌细胞增殖和迁移的能力来解释。此外，通过破坏磷脂酰肌醇 3-激酶介导的途径，PTEN 诱导在介导血管平滑肌细胞增殖和迁移的抑制作用中发挥着至关重要的作用。
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.