Diagnosis and Therapeutic Center, Hypertension and Cardiovascular Prevention Unit, Hotel-Dieu Hospital, AP-HP, Université Paris Descartes, Paris, France.
Centre Hospitalier Universitaire (CHU) Amiens Picardie, Université Picardie Jules Verne (UPJV), 80054 Amiens, France; Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, Poitiers, France.
J Mol Cell Cardiol. 2019 Aug;133:36-46. doi: 10.1016/j.yjmcc.2019.05.024. Epub 2019 May 30.
Atherosclerosis, a chronic inflammatory and age-related disease, is a complex mechanism presenting a dysregulation of vessel structures. During this process, the canonical WNT/β-catenin pathway is increased whereas PPARγ is downregulated. The two systems act in an opposite manner. This paper reviews the opposing interplay of these systems and their metabolic-reprogramming pathway in atherosclerosis. Activation of the WNT/β-catenin pathway enhances the transcription of targets involved in inflammation, endothelial dysfunction, the proliferation of vascular smooth muscle cells, and vascular calcification. This complex mechanism, which is partly controlled by the WNT/β-catenin pathway, presents several metabolic dysfunctions. This phenomenon, called aerobic glycolysis (or the Warburg effect), consists of a shift in ATP production from mitochondrial oxidative phosphorylation to aerobic glycolysis, leading to the overproduction of intracellular lactate. This mechanism is partially due to the injury of mitochondrial respiration and an increase in the glycolytic pathway. In contrast, PPARγ agonists downregulate the WNT/β-catenin pathway. Therefore, the development of therapeutic targets, such as PPARγ agonists, for the treatment of atherosclerosis could be an interesting and innovative way of counteracting the canonical WNT pathway.
动脉粥样硬化是一种慢性炎症性和与年龄相关的疾病，是一种血管结构失调的复杂机制。在这个过程中，经典的 WNT/β-连环蛋白途径增加，而 PPARγ 被下调。这两个系统以相反的方式起作用。本文综述了这两个系统及其在动脉粥样硬化中的代谢重编程途径的相反相互作用。WNT/β-连环蛋白途径的激活增强了参与炎症、内皮功能障碍、血管平滑肌细胞增殖和血管钙化的靶基因的转录。这个复杂的机制，部分受 WNT/β-连环蛋白途径控制，表现出几种代谢功能障碍。这种现象称为有氧糖酵解（或沃伯格效应），它包括从线粒体氧化磷酸化到有氧糖酵解的 ATP 产生的转变，导致细胞内乳酸的过度产生。这种机制部分是由于线粒体呼吸的损伤和糖酵解途径的增加。相反，PPARγ 激动剂下调 WNT/β-连环蛋白途径。因此，开发治疗靶点，如 PPARγ 激动剂，用于治疗动脉粥样硬化可能是一种对抗经典 WNT 途径的有趣和创新的方法。
