Vallée Alexandre, Lecarpentier Yves, Guillevin Rémy, Vallée Jean-Noël
Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France.
Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, 11 Boulevard Marie et Pierre Curie, Poitiers, France.
J Mol Neurosci. 2017 Aug;62(3-4):368-379. doi: 10.1007/s12031-017-0947-4. Epub 2017 Jul 8.
Exudative age-related macular degeneration (AMD) is characterized by molecular mechanisms responsible for the initiation of choroidal neovascularization (CNV). Inflammatory processes are associated with upregulation of the canonical WNT/beta-catenin pathway in exudative AMD. We focus this review on the link between WNT/beta-catenin pathway activation and neovascular progression in exudative AMD through activation of aerobic glycolysis for production of angiogenic factors. Increased WNT/beta-catenin pathway involves hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2). WNT/beta-catenin pathway stimulates PI3K/Akt pathway and then HIF-1alpha which activates glycolytic enzymes: glucose transporter (Glut), pyruvate dehydrogenase kinase 1 (PDK1), lactate dehydrogenase A (LDH-A), and monocarboxylate lactate transporter (MCT-1). This phenomenon is called aerobic glycolysis or the Warburg effect. Consequently, phosphorylation of PDK-1 inhibits the pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-CoA in mitochondria and only a part of acetyl-CoA can enter the tricarboxylic acid cycle. Cytosolic pyruvate is converted into lactate through the action of LDH-A. In exudative AMD, high level of cytosolic lactate is correlated with increase of VEGF expression, the angiogenic factor of CNV. Photoreceptors in retina cells can metabolize glucose through aerobic glycolysis to protect them against oxidative damage, as cancer cells do.
渗出性年龄相关性黄斑变性（AMD）的特征在于引发脉络膜新生血管（CNV）的分子机制。炎症过程与渗出性AMD中经典WNT/β-连环蛋白信号通路的上调有关。本综述聚焦于通过激活有氧糖酵解以产生血管生成因子，探讨WNT/β-连环蛋白信号通路激活与渗出性AMD新生血管进展之间的联系。WNT/β-连环蛋白信号通路增强涉及己糖激酶2（HK2）和丙酮酸激酶M2（PKM2）。WNT/β-连环蛋白信号通路刺激PI3K/Akt信号通路，进而激活低氧诱导因子-1α（HIF-1α），HIF-1α可激活糖酵解酶：葡萄糖转运蛋白（Glut）、丙酮酸脱氢酶激酶1（PDK1）、乳酸脱氢酶A（LDH-A）和单羧酸乳酸转运蛋白（MCT-1）。这种现象被称为有氧糖酵解或瓦伯格效应。因此，PDK-1的磷酸化抑制了丙酮酸脱氢酶复合体（PDH）。这样一来，大部分丙酮酸无法在线粒体中转化为乙酰辅酶A，只有一部分乙酰辅酶A能够进入三羧酸循环。胞质中的丙酮酸通过LDH-A的作用转化为乳酸。在渗出性AMD中，胞质乳酸水平升高与CNV的血管生成因子VEGF表达增加相关。视网膜细胞中的光感受器可以像癌细胞一样通过有氧糖酵解代谢葡萄糖，以保护自身免受氧化损伤。
