FoxO1 inhibition alleviates type 2 diabetes-related diastolic dysfunction by increasing myocardial pyruvate dehydrogenase activity.

Animals Diabetes Mellitus, Experimental / physiopathology Diabetes Mellitus, Type 2 / physiopathology Diabetic Cardiomyopathies / physiopathology Diastole / physiology Fibrosis Forkhead Box Protein O1 / antagonists & inhibitors Glucose / metabolism Homeostasis Lipids / toxicity Male Mice, Inbred C57BL Myocardium / enzymology Pyruvate Dehydrogenase Complex / metabolism
FoxO1 diabetic cardiomyopathy diastolic dysfunction glucose oxidation pyruvate dehydrogenase type 2 diabetes

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
06 04 2021
Historique:
received: 29 09 2020
revised: 11 02 2021
accepted: 11 03 2021
entrez: 7 4 2021
pubmed: 8 4 2021
medline: 27 1 2022
Statut: ppublish

Résumé

Type 2 diabetes (T2D) increases the risk for diabetic cardiomyopathy and is characterized by diastolic dysfunction. Myocardial forkhead box O1 (FoxO1) activity is enhanced in T2D and upregulates pyruvate dehydrogenase (PDH) kinase 4 expression, which inhibits PDH activity, the rate-limiting enzyme of glucose oxidation. Because low glucose oxidation promotes cardiac inefficiency, we hypothesize that FoxO1 inhibition mitigates diabetic cardiomyopathy by stimulating PDH activity. Tissue Doppler echocardiography demonstrates improved diastolic function, whereas myocardial PDH activity is increased in cardiac-specific FoxO1-deficient mice subjected to experimental T2D. Pharmacological inhibition of FoxO1 with AS1842856 increases glucose oxidation rates in isolated hearts from diabetic C57BL/6J mice while improving diastolic function. However, AS1842856 treatment fails to improve diastolic function in diabetic mice with a cardiac-specific FoxO1 or PDH deficiency. Our work defines a fundamental mechanism by which FoxO1 inhibition improves diastolic dysfunction, suggesting that it may be an approach to alleviate diabetic cardiomyopathy.

Identifiants

DOI: 10.1016/j.celrep.2021.108935 PMID: 33826891
pubmed: 33826891
pii: S2211-1247(21)00249-7
doi: 10.1016/j.celrep.2021.108935
pii:
doi:

Substances chimiques

Forkhead Box Protein O1 0
Foxo1 protein, mouse 0
Lipids 0
Pyruvate Dehydrogenase Complex 0
Glucose IY9XDZ35W2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

108935

Subventions

Organisme : CIHR
Pays : Canada

Informations de copyright

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Keshav Gopal (K)

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada.

Rami Al Batran (R)

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada.

Tariq R Altamimi (TR)

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada.

Amanda A Greenwell (AA)

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada.

Christina T Saed (CT)

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada.

Seyed Amirhossein Tabatabaei Dakhili (SA)

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada.

M Toni E Dimaano (MTE)

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.

Yongneng Zhang (Y)

Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada; Department of Medicine, University of Alberta, Edmonton, AB, Canada.

Farah Eaton (F)

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada.

Gopinath Sutendra (G)

Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada; Department of Medicine, University of Alberta, Edmonton, AB, Canada.

John R Ussher (JR)

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada. Electronic address: jussher@ualberta.ca.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › FoxO1 inhibition alleviates type 2...
questionsmedicales.fr › Techniques d'investigation › Modèles animaux › Diabète expérimental › FoxO1 inhibition alleviates type 2...
questionsmedicales.fr › Maladies endocriniennes › Diabète › Diabète de type 2 › FoxO1 inhibition alleviates type 2...
questionsmedicales.fr › Maladies endocriniennes › Diabète › Complications du diabète › Cardiomyopathies diabétiques › FoxO1 inhibition alleviates type 2...
questionsmedicales.fr › Phénomènes physiologiques de l'appareil locomoteur et du système nerveux › Phénomènes physiologiques du système locomoteur › Contraction musculaire › Contraction myocardique › Diastole › FoxO1 inhibition alleviates type 2...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Fibrose › FoxO1 inhibition alleviates type 2...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif hélice ailée › Facteurs de transcription Forkhead › Protéine O1 à motif en tête de fourche › FoxO1 inhibition alleviates type 2...
questionsmedicales.fr › Glucides › Sucres › Oses › Hexose › Glucose › FoxO1 inhibition alleviates type 2...
questionsmedicales.fr › Phénomènes physiologiques › Homéostasie › FoxO1 inhibition alleviates type 2...
questionsmedicales.fr › Lipides › FoxO1 inhibition alleviates type 2...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › FoxO1 inhibition alleviates type 2...
questionsmedicales.fr › Tissus › Muscles › Muscle strié › Myocarde › FoxO1 inhibition alleviates type 2...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Complexes multienzymatiques › Complexe du pyruvate déshydrogénase › FoxO1 inhibition alleviates type 2...