Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Aerobic Glycolysis Hypothesis Through WNT/Beta-Catenin Pathway in Exudative Age-Related Macular Degeneration. 2868 65

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative) phase of the pathology and found higher lactate levels and a shift in the lipoprotein profile (increased VLDL-LDL/HDL ratio). Similar metabolomics changes were detected in the sera of mice subjected to laser-induced choroidal neovascularization (CNV). In this experimental model, we provide evidence for two sites of lactate production: first, a local one in the injured eye, and second a systemic site associated with the recruitment of bone marrow-derived inflammatory cells. Mechanistically, lactate promotes the angiogenic response and M2-like macrophage accumulation in the eyes. The therapeutic potential of our findings is demonstrated by the pharmacological control of lactate levels through pyruvate dehydrogenase kinase (PDK) inhibition by dichloroacetic acid (DCA). Mice treated with DCA exhibited normalized lactate levels and lipoprotein profiles, and inhibited CNV formation. Collectively, our findings implicate the key role of the PDK/lactate axis in AMD pathogenesis and reveal that the regulation of PDK activity has potential therapeutic value in this ocular disease. The results indicate that the lipoprotein profile is a traceable pattern that is worth considering for patient follow-up. KEY MESSAGES: Lactate and lipoprotein profile are associated with the active phase of AMD and CNV development. Lactate is a relevant and functional metabolite correlated with AMD progression. Modulating lactate through pyruvate dehydrogenase kinase led to a decrease of CNV progression. Pyruvate dehydrogenase kinase is a new therapeutic target for neovascular AMD.
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PMID:Pyruvate dehydrogenase kinase/lactate axis: a therapeutic target for neovascular age-related macular degeneration identified by metabolomics. 3307 32