Fischer J W, Kinsella M G, Levkau B, Clowes A W, Wight T N
Department of Pharmacology, Christian Albrechts University, Kiel, Germany.
Arterioscler Thromb Vasc Biol. 2001 May;21(5):777-84. doi: 10.1161/01.atv.21.5.777.
Decorin is a member of the family of small leucine-rich proteoglycans that are present in blood vessels and synthesized by arterial smooth muscle cells (ASMCs). This proteoglycan accumulates in topographically defined regions of atherosclerotic lesions and may play a role in the development of this disease. However, little is known about whether decorin has specific effects on the cellular events that contribute to atherosclerotic lesion formation. In the present study, rat ASMCs were transduced with a retroviral vector (LDSN) that carries the bovine decorin gene. Compared with vector control cells (LXSN), these cells constitutively overexpress decorin, as verified by Northern and Western analysis and by metabolic labeling. Experiments were performed to examine the responsiveness of decorin-overexpressing rat ASMCs to platelet-derived growth factor (PDGF) and transforming growth factor-beta1 (TGF-beta1), 2 growth factors that affect cell proliferation and extracellular matrix production in atherosclerosis. Decorin-overexpressing cells had decreased [(3)H]thymidine incorporation into DNA and increased the levels of the cyclin-dependent kinase inhibitors p21 and p27 in the first 24 hours of response to serum and PDGF-BB. However, these effects of decorin were not apparent at 48 or 72 hours after plating and did not result in reduced growth of decorin-overexpressing cells in response to serum and PDGF-BB. In contrast, the growth response of decorin-overexpressing ASMCs to TGF-beta1, as well as the expression of TGF-beta1-responsive genes, such as plasminogen activator inhibitor-1 and versican (an extracellular matrix proteoglycan), was diminished. These results indicate that decorin selectively inhibits the responsiveness of rat ASMCs to TGF-beta1 and suggests that the induction of constitutive decorin overexpression by ASMCs in vivo may have therapeutic value in the inhibition of TGF-beta1-mediated effects on the development of atherosclerotic lesions.
饰胶蛋白聚糖是富含亮氨酸的小分子蛋白聚糖家族的成员，存在于血管中，由动脉平滑肌细胞（ASMCs）合成。这种蛋白聚糖在动脉粥样硬化病变的特定区域积聚，可能在该疾病的发展中起作用。然而，关于饰胶蛋白聚糖是否对促成动脉粥样硬化病变形成的细胞事件有特定影响，人们知之甚少。在本研究中，用携带牛饰胶蛋白聚糖基因的逆转录病毒载体（LDSN）转导大鼠ASMCs。与载体对照细胞（LXSN）相比，经Northern和Western分析以及代谢标记验证，这些细胞组成性过表达饰胶蛋白聚糖。进行实验以检测过表达饰胶蛋白聚糖的大鼠ASMCs对血小板衍生生长因子（PDGF）和转化生长因子-β1（TGF-β1）的反应性，这两种生长因子影响动脉粥样硬化中的细胞增殖和细胞外基质产生。在对血清和PDGF-BB反应的最初24小时内，过表达饰胶蛋白聚糖的细胞中[³H]胸腺嘧啶掺入DNA减少，细胞周期蛋白依赖性激酶抑制剂p21和p27水平升高。然而，饰胶蛋白聚糖的这些作用在接种后48或72小时并不明显，也未导致过表达饰胶蛋白聚糖的细胞对血清和PDGF-BB的生长减少。相反，过表达饰胶蛋白聚糖的ASMCs对TGF-β1的生长反应以及TGF-β1反应性基因如纤溶酶原激活物抑制剂-1和多功能蛋白聚糖（一种细胞外基质蛋白聚糖）的表达减弱。这些结果表明饰胶蛋白聚糖选择性抑制大鼠ASMCs对TGF-β1的反应性，并提示体内ASMCs组成性过表达饰胶蛋白聚糖在抑制TGF-β1介导的对动脉粥样硬化病变发展的影响方面可能具有治疗价值。
Zotero 插件