FoxO1 inhibition alleviates type 2 diabetes-related diastolic dysfunction by increasing myocardial pyruvate dehydrogenase activity
Keshav Gopal,
Rami Al Batran,
Tariq R. Altamimi,
Amanda A. Greenwell,
Christina T. Saed,
Seyed Amirhossein Tabatabaei Dakhili,
M. Toni E. Dimaano,
Yongneng Zhang,
Farah Eaton,
Gopinath Sutendra,
John R. Ussher
Affiliations
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
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.
