SIRT1/PGC-1α在AGEs促进的血管平滑肌细胞表型转化中的作用研究

It is well confirmed that phenotype transformation of vascular smooth muscle cells (VSMC) is a key cellular event in the pathogenesis of many cardiovascular diseases. It’s also proved that advanced glycation end products (AGEs) could induce the phenotype transformation of VSMC, in which reactive oxygen species play an important role. As mitochondrion is both the major source and a vital attacking target of reactive oxygen species, we investigated the change of mitochondria dynamic proteins during the phenotype transformation of VSMC induced by AGEs. Those observations suggested mitochondria damage occurred. Since mitochondria biogenesis is crucial to the rescue of mitochondria damage and peroxisome proliferators-activated receptor gamma coactivator 1 alpha (PGC-1α) is an essential regulator for mitochondria biogenesis, we hypothesize PGC-1α play a critical role in the phenotype transformation of VSMC induced by AGEs. Silent mating type information regulation 2 homolog- 1(SIRT1) is an upstream regulator of PGC-1α affecting its transcription and activity. We plan to investigate the effect of SIRT1/ PGC-1α axis on phenotype transformation of VSMC induced by Ages, using the gain-of-function and loss-of-function method and molecular biological technology. Accordingly, this study would help to understand the phenotype transformation of VSMC at mitochondria level and might be a solid experimental evidence for future clinical treatment against vascular remodeling.

血管平滑肌细胞（VSMC）的表型转化是血管增殖性疾病发生发展的核心环节，我们前期实验发现晚期糖基化终产物（AGEs）及其受体（RAGE）促进VSMC的表型转化同时改变了线粒体动力学蛋白的表达，提示线粒体发生损伤。线粒体生成在线粒体损伤时尤为重要，过氧化物酶增殖激活受体γ转录共激活因子（PGC-1α）是线粒体生成的重要调节因子，多个研究显示其参与VSMC的收缩蛋白表达、增殖、迁移、分泌炎症因子，据此我们设想PGC-1α是AGEs/RAGE促进VSMC表型转化的关键性分子之一；沉默信息调节因子2相关酶1(SIRT1)是调节PGC-1α转录和活性的上游分子，我们拟通过过表达质粒转染和siRNA基因静默技术，联合细胞和分子生物学方法，观察SIRT1/PGC-1α轴在AGEs/RAGE对VSMC表型转化中的作用。本项目可能为延缓VSMC表型转化的临床干预提供有力的实验室依据。

血管平滑肌细胞（VSMC）是一种多功能间叶细胞，是血管壁的主要成分，也是血管中层唯一的细胞成分。VSMC 的表型发生转化，以及随之发生的异常增殖及由中膜向内膜迁移是高血压病、动脉粥样硬化、血管介入之后再狭窄等增殖性血管疾病的共同病理基础。我们实验发现晚期糖基化终产物（AGEs）通过与其受体（RAGE）结合后，促进VSMC的表型转化同时引起线粒体发生损伤，而过氧化物酶增殖激活受体γ转录共激活因子（PGC-1α）是线粒体生成的重要调节因子，也是AGEs/RAGE促进VSMC表型转化的关键性分子之一；沉默信息调节因子2相关酶1(SIRT1)是调节PGC-1α转录和活性的上游分子，过表达SIRT1后， PGC-1α的表达增加，抑制AGEs诱导的VSMC表型转化，并对线粒体功能障碍发挥保护作用。因此，SIRT1/PGC-1α轴在AGEs/RAGE对VSMC表型转化中的重要作用得以证实。PGC-1α 很可能成为延缓或逆转 VSMC 表型转化、防治血管增殖性疾病、线粒体药物中的一个重要靶点，这为将来的临床干预提供有力的实验依据。