FOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes
Open Access
- 25 May 2020
- journal article
- research article
- Published by Wiley in Journal of Cellular and Molecular Medicine
- Vol. 24 (14), 7850-7861
- https://doi.org/10.1111/jcmm.15418
Abstract
Forkhead 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.Keywords
Funding Information
- National Natural Science Foundation of China-Yunnan Joint Fund (NSFC 81670770)
This publication has 43 references indexed in Scilit:
- Taking Diabetes to Heart—Deregulation of Myocardial Lipid Metabolism in Diabetic CardiomyopathyJournal of the American Heart Association, 2013
- Susceptibility to myocardial ischemia reperfusion injury at early stage of type 1 diabetes in ratsCardiovascular Diabetology, 2013
- Targeting mitochondrial oxidative metabolism as an approach to treat heart failureBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2013
- FoxO1 is crucial for sustaining cardiomyocyte metabolism and cell survivalCardiovascular Research, 2012
- Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in miceJCI Insight, 2012
- FoxO1, the transcriptional chief of staff of energy metabolismBone, 2012
- FoxO transcription factors; Regulation by AKT and 14-3-3 proteinsBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2011
- Peroxisome proliferator activated receptor α (PPARα) and PPAR gamma coactivator (PGC-1α) induce carnitine palmitoyltransferase IA (CPT-1A) via independent gene elementsMolecular and Cellular Endocrinology, 2010
- Disruption of Sarcolemmal ATP-Sensitive Potassium Channel Activity Impairs the Cardiac Response to Systolic OverloadCirculation Research, 2008
- Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathyAmerican Journal of Physiology-Heart and Circulatory Physiology, 2008