Cardiac metabolism as a driver and therapeutic target of myocardial infarction
Zuurbier, Coert J. (University of Amsterdam)
Bertrand, Luc (Université catholique de Louvain)
Beauloye, Christoph R. (Cliniques Universitaires Saint-Luc)
Andreadou, Ioanna (National and Kapodistrian University of Athens)
Ruiz Meana, Marisol (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Jespersen, Nichlas R. (Aarhus University Hospital (Aarhus, Dinamarca))
Kula-Alwar, Duvaraka (University of Cambridge)
Prag, Hiran A. (University of Cambridge)
Eric Botker, Hans (Aarhus University Hospital (Aarhus, Dinamarca))
Dambrova, Maija (Latvian Institute of Organic Synthesis)
Montessuit, Christophe (University of Geneva School of Medicine)
Kaambre, Tuuli (National Institute of Chemical Physics and Biophysics)
Liepinsh, Edgars (Latvian Institute of Organic Synthesis)
Brookes, Paul S. (University of Rochester Medical Center)
Krieg, Thomas (University of Cambridge)
Universitat Autònoma de Barcelona

Data:	2020
Resum:	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 FF-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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article de revisió ; Article ; Versió publicada
Matèria:	Ischemia ; Metabolism ; Mitochondria
Publicat a:	Journal of Cellular and Molecular Medicine, Vol. 24 (may 2020) , p. 5937-5954, ISSN 1582-4934

DOI: 10.1111/jcmm.15180
PMID: 32384583

18 p, 591.8 KB

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