Arany Zoltan, Foo Shi-Yin, Ma Yanhong, Ruas Jorge L, Bommi-Reddy Archana, Girnun Geoffrey, Cooper Marcus, Laznik Dina, Chinsomboon Jessica, Rangwala Shamina M, Baek Kwan Hyuck, Rosenzweig Anthony, Spiegelman Bruce M
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature. 2008 Feb 21;451(7181):1008-12. doi: 10.1038/nature06613.
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. Here we show that the transcriptional coactivator PGC-1alpha (peroxisome-proliferator-activated receptor-gamma coactivator-1alpha), a potent metabolic sensor and regulator, is induced by a lack of nutrients and oxygen, and PGC-1alpha powerfully regulates VEGF expression and angiogenesis in cultured muscle cells and skeletal muscle in vivo. PGC-1alpha-/- 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-1alpha in skeletal muscle is protective. Surprisingly, the induction of VEGF by PGC-1alpha does not involve the canonical hypoxia response pathway and hypoxia inducible factor (HIF). Instead, PGC-1alpha 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-1alpha 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-1alpha may provide a novel therapeutic target for treating ischaemic diseases.
心脏、大脑和肢体的缺血是全球发病和死亡的主要原因。缺氧刺激血管内皮生长因子（VEGF）及其他血管生成因子的分泌，导致新血管形成并抵御缺血性损伤。在此我们表明，转录共激活因子PGC-1α（过氧化物酶体增殖物激活受体γ共激活因子-1α），一种强大的代谢传感器和调节因子，可由营养物质和氧气的缺乏诱导产生，并且PGC-1α在体外培养的肌肉细胞和体内骨骼肌中有力地调节VEGF表达和血管生成。PGC-1α基因敲除小鼠在缺血损伤后，肢体无法以正常方式重建血流，而PGC-1α在骨骼肌中的转基因表达具有保护作用。令人惊讶的是，PGC-1α对VEGF的诱导不涉及经典的缺氧反应途径和缺氧诱导因子（HIF）。相反，PGC-1α在VEGF基因启动子和第一个内含子中的一个簇内发现的保守结合位点上，与孤儿核受体ERR-α（雌激素相关受体-α）共同激活。因此，PGC-1α和ERR-α作为响应运动及其他刺激的线粒体功能主要调节因子，还控制着一条输送所需氧气和底物的新型血管生成途径。PGC-1α可能为治疗缺血性疾病提供一个新的治疗靶点。
