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http://purl.uniprot.org/citations/22436846http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/22436846http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/22436846http://www.w3.org/2000/01/rdf-schema#comment"

Aims

During reperfusion of the ischaemic myocardium, fatty acid oxidation rates quickly recover, while glucose oxidation rates remain depressed. Direct stimulation of glucose oxidation via activation of pyruvate dehydrogenase (PDH), or secondary to an inhibition of malonyl CoA decarboxylase (MCD), improves cardiac functional recovery during reperfusion following ischaemia. However, the effects of such interventions on the evolution of myocardial infarction are unknown. The purpose of this study was to determine whether infarct size is decreased in response to increased glucose oxidation.

Methods and results

In vivo, direct stimulation of PDH in mice with the PDH kinase (PDHK) inhibitor, dichloroacetate, significantly decreased infarct size following temporary ligation of the left anterior descending coronary artery. These results were recapitulated in PDHK 4-deficient (PDHK4-/-) mice, which have enhanced myocardial PDH activity. These interventions also protected against ischaemia/reperfusion injury in the working heart, and dichloroacetate failed to protect in PDHK4-/-mice. In addition, there was a dramatic reduction in the infarct size in malonyl CoA decarboxylase-deficient (MCD-/-) mice, in which glucose oxidation rates are enhanced (secondary to an inhibition of fatty acid oxidation) relative to their wild-type littermates (10.8 ± 3.8 vs. 39.5 ± 4.7%). This cardioprotective effect in MCD-/-mice was associated with increased PDH activity in the ischaemic area at risk (1.89 ± 0.18 vs. 1.52 ± 0.05 μmol/g wet weight/min).

Conclusion

These findings demonstrate that stimulating glucose oxidation via targeting either PDH or MCD decreases the infarct size, validating the concept that optimizing myocardial metabolism is a novel therapy for ischaemic heart disease."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.org/dc/terms/identifier"doi:10.1093/cvr/cvs129"xsd:string
http://purl.uniprot.org/citations/22436846http://purl.org/dc/terms/identifier"doi:10.1093/cvr/cvs129"xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Harris R.A."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Harris R.A."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Wang W."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Wang W."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Dyck J.R."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Dyck J.R."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Oka T."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Oka T."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Lopaschuk G.D."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Lopaschuk G.D."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Gandhi M."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Gandhi M."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Clanachan A.S."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Clanachan A.S."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Jaswal J.S."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Jaswal J.S."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Keung W."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Keung W."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Samokhvalov V."xsd:string
http://purl.uniprot.org/citations/22436846http://purl.uniprot.org/core/author"Samokhvalov V."xsd:string
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