Figure 2.

Major features and mechanistic basis of the adaptive cardiac metabolism under chronic hypoxia. Chronic hypoxia leads to increased level and stabilization of HIF-1α, which upregulates the expression of glucose transporter 1 (GLUT1), hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase isozyme M2 (PKM2), lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase 1 (PDK1), glycogen synthase 1 (GYS1), and phosphoglucomutase (PGM). These changes lead to increase in glucose uptake, glycolysis, and glycogen synthesis. Additionally, chronic hypoxia decreases PPARα and PGC-1α levels, which decrease fatty acid uptake and β-oxidation through downregulation of fatty acid transport protein (FATP), carnitine palmitoyl transferase 1 (CPT1), medium chain acyl-CoA dehydrogenase (MCAD), long chain acyl-CoA dehydrogenase (LCAD) and uncoupling protein 3 (UCP3). Decreased UCP3 level is associated with less proton leak and increased mitochondrial efficiency for oxygen utilization. Of note, pyruvate dehydrogenase kinase 4 (PDK4) is reduced by downregulated PPARα, which activates pyruvate dehydrogenase (PDH) activity. Decreased PGC-1α reduces mitochondrial biosynthesis of components of electron transport chain, which reduces the generation of reactive oxygen species (ROS). Moreover, protein kinase C epsilon (PKCε) is activated under chronic hypoxia, which phosphorylates glycogen synthase kinase 3β (GSK3β) and reduces its phosphorylation on HIF-1α and GYS1. As the phosphorylation of HIF-1α and GYS1 leads to inhibition of their activities, activated PKCε promotes HIF-1α signaling and glycogen storage under chronic hypoxia. Collectively, these metabolic changes result in increased reliance on carbohydrates over fatty acids for ATP production. Other notable metabolic features include smaller size of mitochondria and decreased phosphocreatine (PCr)/ATP ratio. See text for further details. MPC, mitochondrial pyruvate carrier.