HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α
HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α
复制标题
DOI：
10.1038/nature06613
复制
发表时间：
2008-02-21
期刊：
影响因子：
64.8
通讯作者：
Spiegelman, Bruce M.
中科院分区：
文献类型：
--
作者：
Arany, Zoltan;Foo, Shi-Yin;Spiegelman, Bruce M.
心脏、大脑和四肢的缺血是全世界发病率和死亡率的主要原因。缺氧刺激血管内皮生长因子（VEGF）和其他血管生成因子的分泌，导致新血管形成和防止缺血性损伤（1）。在这里，我们表明转录辅激活因子PGC-1 α（过氧化物酶体-增殖物-激活受体-γ辅激活因子-1 α）是一种有效的代谢传感器和调节因子（2），是由营养物质和氧气的缺乏诱导的，并且PGC-1 α在体内培养的肌肉细胞和骨骼肌中有力地调节血管内皮生长因子的表达和血管生成。PGC-1 α（-/-）小鼠在缺血性损伤后表现出明显的不能以正常方式重建肢体的血流，而骨骼肌中PGC-1 α的转基因表达具有保护作用。令人惊讶的是，PGC-1 α对VEGF的诱导并不涉及典型的缺氧反应途径和缺氧诱导因子（HIF）。相反，PGC-1 α在启动子和VEGF基因第一内含子内的簇中发现的保守结合位点上共激活孤儿核受体ERR-α（雌激素相关受体-α）。因此，PGC-1 α和ERR-α，线粒体功能对运动和其他刺激的主要调节剂，也控制着一种新的血管生成途径，该途径提供所需的氧气和底物。PGC-1 α可能为治疗缺血性疾病提供新的治疗靶点。
Ischaemia of the heart, brain and limbs is a leading cause of morbidity and mortality worldwide. Hypoxia stimulates the secretion of vascular endothelial growth factor ( VEGF) and other angiogenic factors, leading to neovascularization and protection against ischaemic injury(1). Here we show that the transcriptional coactivator PGC-1 alpha ( peroxisome- proliferator- activated receptor-gamma coactivator-1 alpha), a potent metabolic sensor and regulator(2), is induced by a lack of nutrients and oxygen, and PGC-1 alpha powerfully regulates VEGF expression and angiogenesis in cultured muscle cells and skeletal muscle in vivo. PGC-1 alpha(-/-) mice show a striking failure to reconstitute blood flow in a normal manner to the limb after an ischaemic insult, whereas transgenic expression of PGC-1 alpha in skeletal muscle is protective. Surprisingly, the induction of VEGF by PGC-1 alpha does not involve the canonical hypoxia response pathway and hypoxia inducible factor ( HIF). Instead, PGC-1 alpha coactivates the orphan nuclear receptor ERR-alpha ( oestrogen- related receptor- alpha) on conserved binding sites found in the promoter and in a cluster within the first intron of the VEGF gene. Thus, PGC-1 alpha and ERR-alpha, major regulators of mitochondrial function in response to exercise and other stimuli, also control a novel angiogenic pathway that delivers needed oxygen and substrates. PGC-1 alpha may provide a novel therapeutic target for treating ischaemic diseases.