Glucose metabolism and cardiac hypertrophy

Abstract

The most notable change in the metabolic profile of hypertrophied hearts is an increased reliance on glucose with an overall reduced oxidative metabolism, i.e. a reappearance of the foetal metabolic pattern. In animal models, this change is attributed to the down-regulation of the transcriptional cascades promoting gene expression for fatty acid oxidation and mitochondrial oxidative phosphorylation in adult hearts. Impaired myocardial energetics in cardiac hypertrophy also triggers AMP-activated protein kinase (AMPK), leading to increased glucose uptake and glycolysis. Aside from increased reliance on glucose as an energy source, changes in other glucose metabolism pathways, e.g. the pentose phosphate pathway, the glucosamine biosynthesis pathway, and anaplerosis, are also noted in the hypertrophied hearts. Studies using transgenic mouse models and pharmacological compounds to mimic or counter the switch of substrate preference in cardiac hypertrophy have demonstrated that increased glucose metabolism in adult heart is not harmful and can be beneficial when it provides sufficient fuel for oxidative metabolism. However, improvement in the oxidative capacity and efficiency rather than the selection of the substrate is likely the ultimate goal for metabolic therapies.

Figure 1

Glucose metabolism pathways. 6-PG, 6-phosphogluconate; 6-PGL, 6-phosphoglucono-δ-lactone; AR, aldose reductase; F-6-P, fructose-6-phosphate; F-1,6,-BP, fructose-1,6-bisphosphate; G-6-P, glucose-6-phosphate; GFAT, glutamine fructose-6-phosphate amidotransferase; G6PD: glucose-6-phosphate dehydrogenase; NAD+, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADP+, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; R-5-P, ribose-5-phosphate; SDH, sorbitol dehydrogenase; UDPGlcNAc, uridine diphosphate-N-acetylglucosamine; X-5-P, xylose-5-phosphate.

Figure 2

Altered glucose metabolism in cardiac hypertrophy. Key changes in the metabolic pathway have been colour coded. Green: increased; Red: decreased; Blue: no change; Black: unknown. F-6-P, fructose-6-phosphate; G-6-P, glucose-6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; GFAT, glutamine fructose-6-phosphate amidotransferase; GLUT, glucose transporter; LDH, lactate dehydrogenase; ME, malic enzyme; NADH, reduced nicotinamide adenine dinucleotide; OMC, oxoglutarate-malate carrier; TCA, tricarboxylic acid.