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Article: FOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes

TitleFOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes
Authors
Keywordsdiabetic cardiomyopathy
FOXO1
oxidative metabolism
Issue Date2020
PublisherWiley Open Access for Foundation for Cellular and Molecular Medicine. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=1582-1838
Citation
Journal of Cellular and Molecular Medicine, 2020, v. 24 n. 14, p. 7850-7861 How to Cite?
AbstractForkhead box protein O1 (FOXO1), a nuclear transcription factor, is preferably activated in the myocardium of diabetic mice. However, its role and mechanism in the development of diabetic cardiomyopathy in non‐obese insulin‐deficient diabetes are unclear. We hypothesized that cardiac FOXO1 over‐activation was attributable to the imbalanced myocardial oxidative metabolism and mitochondrial and cardiac dysfunction in type 1 diabetes. FOXO1‐selective inhibitor AS1842856 was administered to streptozotocin‐induced diabetic (D) rats, and cardiac functions, mitochondrial enzymes PDK4 and CPT1 and mitochondrial function were assessed. Primary cardiomyocytes isolated from non‐diabetic control (C) and D rats were treated with or without 1 µM AS1842856 and underwent Seahorse experiment to determine the effects of glucose, palmitate and pyruvate on cardiomyocyte bioenergetics. The results showed diabetic hearts displayed elevated FOXO1 nuclear translocation, concomitant with cardiac and mitochondrial dysfunction (manifested as elevated mtROS level and reduced mitochondrial membrane potential) and increased cell apoptosis (all P < .05, D vs C). Diabetic myocardium showed impaired glycolysis, glucose oxidation and elevated fatty acid oxidation and enhanced PDK4 and CPT1 expression. AS1842856 attenuated or prevented all these changes except for glycolysis. We concluded that FOXO1 activation, through stimulating PDK4 and CPT1, shifts substrate selection from glucose to fatty acid and causes mitochondrial and cardiac dysfunction.
Persistent Identifierhttp://hdl.handle.net/10722/293254
ISSN
2019 Impact Factor: 4.486
2015 SCImago Journal Rankings: 1.941
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYAN, D-
dc.contributor.authorCai, Y-
dc.contributor.authorLuo, J-
dc.contributor.authorLiu, J-
dc.contributor.authorLi, X-
dc.contributor.authorYing, F-
dc.contributor.authorXIE, X-
dc.contributor.authorXu, A-
dc.contributor.authorMa, X-
dc.contributor.authorXia, Z-
dc.date.accessioned2020-11-23T08:14:04Z-
dc.date.available2020-11-23T08:14:04Z-
dc.date.issued2020-
dc.identifier.citationJournal of Cellular and Molecular Medicine, 2020, v. 24 n. 14, p. 7850-7861-
dc.identifier.issn1582-1838-
dc.identifier.urihttp://hdl.handle.net/10722/293254-
dc.description.abstractForkhead box protein O1 (FOXO1), a nuclear transcription factor, is preferably activated in the myocardium of diabetic mice. However, its role and mechanism in the development of diabetic cardiomyopathy in non‐obese insulin‐deficient diabetes are unclear. We hypothesized that cardiac FOXO1 over‐activation was attributable to the imbalanced myocardial oxidative metabolism and mitochondrial and cardiac dysfunction in type 1 diabetes. FOXO1‐selective inhibitor AS1842856 was administered to streptozotocin‐induced diabetic (D) rats, and cardiac functions, mitochondrial enzymes PDK4 and CPT1 and mitochondrial function were assessed. Primary cardiomyocytes isolated from non‐diabetic control (C) and D rats were treated with or without 1 µM AS1842856 and underwent Seahorse experiment to determine the effects of glucose, palmitate and pyruvate on cardiomyocyte bioenergetics. The results showed diabetic hearts displayed elevated FOXO1 nuclear translocation, concomitant with cardiac and mitochondrial dysfunction (manifested as elevated mtROS level and reduced mitochondrial membrane potential) and increased cell apoptosis (all P < .05, D vs C). Diabetic myocardium showed impaired glycolysis, glucose oxidation and elevated fatty acid oxidation and enhanced PDK4 and CPT1 expression. AS1842856 attenuated or prevented all these changes except for glycolysis. We concluded that FOXO1 activation, through stimulating PDK4 and CPT1, shifts substrate selection from glucose to fatty acid and causes mitochondrial and cardiac dysfunction.-
dc.languageeng-
dc.publisherWiley Open Access for Foundation for Cellular and Molecular Medicine. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=1582-1838-
dc.relation.ispartofJournal of Cellular and Molecular Medicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectdiabetic cardiomyopathy-
dc.subjectFOXO1-
dc.subjectoxidative metabolism-
dc.titleFOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes-
dc.typeArticle-
dc.identifier.emailXu, A: amxu@hkucc.hku.hk-
dc.identifier.emailXia, Z: zyxia@hkucc.hku.hk-
dc.identifier.authorityXu, A=rp00485-
dc.identifier.authorityXia, Z=rp00532-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1111/jcmm.15418-
dc.identifier.pmid32450616-
dc.identifier.pmcidPMC7348139-
dc.identifier.scopuseid_2-s2.0-85085623869-
dc.identifier.hkuros319756-
dc.identifier.volume24-
dc.identifier.issue14-
dc.identifier.spage7850-
dc.identifier.epage7861-
dc.identifier.isiWOS:000535124300001-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl1582-1838-

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