Inhibition of collagen synthesis, smooth muscle cell proliferation, and injury-induced intimal hyperplasia by halofuginone
Inhibition of collagen synthesis, smooth muscle cell proliferation, and injury-induced intimal hyperplasia by halofuginone
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DOI：
10.1161/01.atv.17.1.194
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发表时间：
1997-01-01
影响因子：
8.7
通讯作者：
Vlodavsky, I
中科院分区：
文献类型：
--
作者：
Nagler, A;Miao, HQ;Vlodavsky, I
血管平滑肌细胞（SMC）的增殖和细胞外基质（ECM）成分在动脉壁内的积聚是血管增生性疾病如动脉硬化和血管成形术后再狭窄的重要病因。原纤维和非原纤维胶原是ECM的主要成分，其调节细胞形状和增殖反应，从而促进内膜增生的发病机制。常山酮，一种抗球虫喹唑啉酮衍生物，抑制I型胶原基因表达。我们研究了常山酮对（1）来自同一标本并在体外维持的牛主动脉内皮细胞和SMC的增殖，（3）ECM沉积和I型胶原合成和基因表达，以及（3）体内损伤诱导的内膜增生的影响。DNA合成和增殖的血管平滑肌细胞在血清或碱性成纤维细胞生长因子被废除的存在下，低至0.1微克/毫升卤夫酮，这种抑制作用是可逆的化合物去除后。在相同条件下，常山酮对相应的血管内皮细胞产生相对较小的抗增殖作用。常山酮还抑制血管SMC的ECM组分的合成和沉积，如硫酸化蛋白聚糖和I型胶原合成和基因表达的量的实质性减少所示。局部给药常山酮在兔耳模型挤压伤诱导的动脉内膜增生导致内膜增厚减少50%，通过测量的新生内膜/中膜比的形态学分析。常山酮对血管平滑肌细胞与内皮细胞的不同抑制作用，其对ECM沉积和I型胶原合成的抑制，以及其减弱损伤诱导的内膜增生的能力，可能使常山酮单独或与其他抗增殖化合物组合作为预防动脉狭窄和加速动脉粥样硬化的潜在候选物。
Proliferation of vascular smooth muscle cells (SMCs) and accumulation of extracellular matrix (ECM) components within the arterial wall in response to local injury are important etiologic factors in vascular proliferative disorders such as arteriosclerosis and restenosis after angioplasty. Fibrillar and nonfibrillar collagens are major constituents of the ECM that modulate cell shape and proliferative responses and thereby contribute to the pathogenesis of intimal hyperplasia. Halofuginone, an anticoccidial quinoazolinone derivative, inhibits collagen type I gene expression. We investigated the effect of halofuginone on (1) proliferation of bovine aortic endothelial cells and SMCs derived from the same specimen and maintained in vitro, (3) ECM deposition and collagen type I synthesis and gene expression, and (3) injury-induced intimal hyperplasia in vivo. DNA synthesis and proliferation of vascular SMCs in response to serum or basic fibroblast growth factor were abrogated in the presence of as little as 0.1 mu g/mL halofuginone; this inhibition was reversible upon removal of the compound. Under the same conditions, halofuginone exerted a relatively small antiproliferative effect on the respective vascular endothelial cells. Halofuginone also inhibited the synthesis and deposition of ECM components by vascular SMCs as indicated both by a substantial reduction in the amount of sulfated proteoglycans and collagen type I synthesis and gene expression. Local administration of halofuginone in the rabbit ear model of crush injury-induced arterial intimal hyperplasia resulted in a 50% reduction in intimal thickening as measured by a morphometric analysis of the neointima/media ratio. The differential inhibitory effect of halofuginone on vascular SMCs versus endothelial cells, its inhibition of ECM deposition and collagen type I synthesis, and its ability to attenuate injury-induced intimal hyperplasia may place halofuginone alone or in combination with other antiproliferative compounds as a potential candidate for prevention of arterial stenosis and accelerated atherosclerosis.