Adaptive Cardiac Metabolism Under Chronic Hypoxia: Mechanism and Clinical Implications

Abstract

Chronic hypoxia is an essential component in many cardiac diseases. The heart consumes a substantial amount of energy and it is important to maintain the balance of energy supply and demand when oxygen is limited. Previous studies showed that the heart switches from fatty acid to glucose to maintain metabolic efficiency in the adaptation to chronic hypoxia. However, the underlying mechanism of this adaptive cardiac metabolism remains to be fully characterized. Moreover, how the altered cardiac metabolism affects the heart function in patients with chronic hypoxia has not been discussed in the current literature. In this review, we summarized new findings from animal and human studies to illustrate the mechanism underlying the adaptive cardiac metabolism under chronic hypoxia. Clinical focus is given to certain patients that are subject to the impact of chronic hypoxia, and potential treatment strategies that modulate cardiac metabolism and may improve the heart function in these patients are also summarized.

Keywords: HIF-1α; cardiac metabolism; chronic hypoxia; heart failure; heart function; metabolic efficiency.

Figure 1

The involvement of chronic hypoxia in different clinical scenarios.

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.

Figure 3

A proposed regulation model of cardiac PDH activity under chronic hypoxia. The activity of PDH is mainly determined by reversible phosphorylation from PDK and PDP. PDK1 is oxygen sensitive and transcriptionally regulated by HIF-1α. PDK4 is nutrient sensitive, its expression is transcriptionally regulated by PPARα and its activity is allosterically regulated by FFA and metabolites (NADH, acetyl-CoA) derived from the oxidation of pyruvate or FFA. Under chronic hypoxia, elevated HIF-1α and decreased PPARα have opposing effects on the expression of PDK1 and PDK4. However, the activity of PDK4 is also affected by decreased levels of fatty acids and metabolites derived from β-oxidation. Hence, PDK4 appears to be more involved in the regulation of PDH activity in the chronically hypoxic heart. Decreased expression and activity of PDK4 reduce the phosphorylation of PDH, which maintains its active state. PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PDP, pyruvate dehydrogenase phosphatase; Pi, inorganic phosphate; FFA, free fatty acids; NADH, nicotinamide adenine dinucleotide.

Figure 4

Potential strategies available to modulate the adaptive cardiac metabolism under chronic hypoxia.