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

Cell Reports, Vol. 35 (2021)

Mots clés
Auteurs
  • Keshav Gopal
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
  • Yongneng Zhang
  • Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada; Department of Medicine, University of Alberta, Edmonton, AB, Canada
  • Farah Eaton
  • 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
  • Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada; Department of Medicine, University of Alberta, Edmonton, AB, Canada
  • John R. Ussher
  • 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; Corresponding author

Résumé

Summary: 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.

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