Repository logo
 

Cardiac metabolism as a driver and therapeutic target of myocardial infarction.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Zuurbier, Coert J 
Bertrand, Luc 
Beauloye, Christoph R 
Andreadou, Ioanna 
Ruiz-Meana, Marisol 

Abstract

Reducing infarct size during a cardiac ischaemic-reperfusion episode is still of paramount importance, because the extension of myocardial necrosis is an important risk factor for developing heart failure. Cardiac ischaemia-reperfusion injury (IRI) is in principle a metabolic pathology as it is caused by abruptly halted metabolism during the ischaemic episode and exacerbated by sudden restart of specific metabolic pathways at reperfusion. It should therefore not come as a surprise that therapy directed at metabolic pathways can modulate IRI. Here, we summarize the current knowledge of important metabolic pathways as therapeutic targets to combat cardiac IRI. Activating metabolic pathways such as glycolysis (eg AMPK activators), glucose oxidation (activating pyruvate dehydrogenase complex), ketone oxidation (increasing ketone plasma levels), hexosamine biosynthesis pathway (O-GlcNAcylation; administration of glucosamine/glutamine) and deacetylation (activating sirtuins 1 or 3; administration of NAD+ -boosting compounds) all seem to hold promise to reduce acute IRI. In contrast, some metabolic pathways may offer protection through diminished activity. These pathways comprise the malate-aspartate shuttle (in need of novel specific reversible inhibitors), mitochondrial oxygen consumption, fatty acid oxidation (CD36 inhibitors, malonyl-CoA decarboxylase inhibitors) and mitochondrial succinate metabolism (malonate). Additionally, protecting the cristae structure of the mitochondria during IR, by maintaining the association of hexokinase II or creatine kinase with mitochondria, or inhibiting destabilization of FO F1 -ATPase dimers, prevents mitochondrial damage and thereby reduces cardiac IRI. Currently, the most promising and druggable metabolic therapy against cardiac IRI seems to be the singular or combined targeting of glycolysis, O-GlcNAcylation and metabolism of ketones, fatty acids and succinate.

Description

Keywords

ischemia, metabolism, mitochondria, Animals, Energy Metabolism, Humans, Mitochondria, Heart, Molecular Targeted Therapy, Myocardial Infarction, Myocardial Reperfusion Injury, Myocardium

Journal Title

J Cell Mol Med

Conference Name

Journal ISSN

1582-1838
1582-4934

Volume Title

24

Publisher

Wiley