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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model
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A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model

机译：法尼基转移酶抑制剂可预防早衰小鼠模型中心血管疾病的发作和晚期进展

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摘要

Hutchinson-Gilford progeria syndrome (HGPS) is the most dramatic form of human premature aging. Death occurs at a mean age of 13 years, usually from heart attack or stroke. Almost all cases of HGPS are caused by a de novo point mutation in the lamin A (LMNA) gene that results in production of a mutant lamin A protein termed progerin. This protein is permanently modified by a lipid farnesyl group, and acts as a dominant negative, disrupting nuclear structure. Treatment with farnesyltransferase inhibitors (FTIs) has been shown to prevent and even reverse this nuclear abnormality in cultured HGPS fibroblasts. We have previously created a mouse model of HGPS that shows progressive loss of vascular smooth muscle cells in the media of the large arteries, in a pattern that is strikingly similar to the cardiovascular disease seen in patients with HGPS. Here we show that the dose-dependent administration of the FTI tipifarnib (R115777, Zarnestra) to this HGPS mouse model can significantly prevent both the onset of the cardiovascular phenotype as well as the late progression of existing cardiovascular disease. These observations provide encouraging evidence for the current clinical trial of FTIs for this rare and devastating disease.
机译：Hutchinson-Gilford早衰综合症（HGPS）是人类过早衰老的最剧烈形式。死亡通常发生于心脏病发作或中风，平均年龄为13岁。几乎所有的HGPS病例都是由lamin A（LMNA）基因的从头突变引起的，这种突变导致产生称为progerin的突变lamin A蛋白。该蛋白质被脂质法呢基基团永久修饰，并作为显性负性，破坏核结构。研究表明，使用法呢基转移酶抑制剂（FTIs）可以预防甚至逆转培养的HGPS成纤维细胞中的这种核异常。我们以前已经创建了一种HGPS小鼠模型，该模型显示出大动​​脉介质中血管平滑肌细胞的逐渐丧失，其模式与HGPS患者所见的心血管疾病极为相似。在这里，我们显示FTI替比法尼（R115777，Zarnestra）对这种HGPS小鼠模型的剂量依赖性给药可以显着预防心血管表型的发作以及现有心血管疾病的晚期发展。这些观察结果为这种罕见和破坏性疾病的FTIs的当前临床试验提供了令人鼓舞的证据。

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