title: Activation of Foxo1 by insulin resistance promotes cardiac dysfunction and β-myosin heavy chain gene expression.
abstract: BACKGROUND
  Heart failure is a leading cause of morbidity and mortality in the USA and is closely associated with diabetes mellitus. The molecular link between diabetes mellitus and heart failure is incompletely understood. We recently demonstrated that insulin receptor substrates 1, 2 (IRS1, 2) are key components of insulin signaling and loss of IRS1 and IRS2 mediates insulin resistance, resulting in metabolic dysregulation and heart failure, which is associated with downstream Akt inactivation and in turn activation of the forkhead transcription factor Foxo1.
  
  
  RESULTS
  To determine the role of Foxo1 in control of heart failure in insulin resistance and diabetes mellitus, we generated mice lacking Foxo1 gene specifically in the heart. Mice lacking both IRS1 and IRS2 in adult hearts exhibited severe heart failure and a remarkable increase in the β-isoform of myosin heavy chain (β-MHC) gene expression, whereas deletion of cardiac Foxo1 gene largely prevented the heart failure and resulted in a decrease in β-MHC expression. The effect of Foxo1 deficiency on rescuing cardiac dysfunction was also observed in db/db mice and high-fat diet mice. Using cultures of primary ventricular cardiomyocytes, we found that Foxo1 interacts with the promoter region of β-MHC and stimulates gene expression, mediating an effect of insulin that suppresses β-MHC expression.
  
  
  CONCLUSIONS
  Our study suggests that Foxo1 has important roles in promoting diabetic cardiomyopathy and controls β-MHC expression in the development of cardiac dysfunction. Targeting Foxo1 and its regulation will provide novel strategies in preventing metabolic and myocardial dysfunction and influencing MHC plasticity in diabetes mellitus.
authors.affiliation: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Baylor Scott & White Health, Central Texas Veterans Health Care System, Temple (Y.Q., Q.Z., K.Z., C.T., Y.W., R.K., K.M.B., Z.X., S.C., S.G.); and Department of Pharmacology, Hebei United University, Tangshan, China (Y.Q.).
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Qi
authors.affiliation: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Baylor Scott & White Health, Central Texas Veterans Health Care System, Temple (Y.Q., Q.Z., K.Z., C.T., Y.W., R.K., K.M.B., Z.X., S.C., S.G.); and Department of Pharmacology, Hebei United University, Tangshan, China (Y.Q.).
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Baylor Scott & White Health, Central Texas Veterans Health Care System, Temple (Y.Q., Q.Z., K.Z., C.T., Y.W., R.K., K.M.B., Z.X., S.C., S.G.); and Department of Pharmacology, Hebei United University, Tangshan, China (Y.Q.).
authors.forename: Kebin
authors.initials: K
authors.lastname: Zhang
authors.affiliation: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Baylor Scott & White Health, Central Texas Veterans Health Care System, Temple (Y.Q., Q.Z., K.Z., C.T., Y.W., R.K., K.M.B., Z.X., S.C., S.G.); and Department of Pharmacology, Hebei United University, Tangshan, China (Y.Q.).
authors.forename: Candice
authors.initials: C
authors.lastname: Thomas
authors.affiliation: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Baylor Scott & White Health, Central Texas Veterans Health Care System, Temple (Y.Q., Q.Z., K.Z., C.T., Y.W., R.K., K.M.B., Z.X., S.C., S.G.); and Department of Pharmacology, Hebei United University, Tangshan, China (Y.Q.).
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Baylor Scott & White Health, Central Texas Veterans Health Care System, Temple (Y.Q., Q.Z., K.Z., C.T., Y.W., R.K., K.M.B., Z.X., S.C., S.G.); and Department of Pharmacology, Hebei United University, Tangshan, China (Y.Q.).
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Baylor Scott & White Health, Central Texas Veterans Health Care System, Temple (Y.Q., Q.Z., K.Z., C.T., Y.W., R.K., K.M.B., Z.X., S.C., S.G.); and Department of Pharmacology, Hebei United University, Tangshan, China (Y.Q.).
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Baker
authors.affiliation: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Baylor Scott & White Health, Central Texas Veterans Health Care System, Temple (Y.Q., Q.Z., K.Z., C.T., Y.W., R.K., K.M.B., Z.X., S.C., S.G.); and Department of Pharmacology, Hebei United University, Tangshan, China (Y.Q.).
authors.forename: Zihui
authors.initials: Z
authors.lastname: Xu
authors.affiliation: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Baylor Scott & White Health, Central Texas Veterans Health Care System, Temple (Y.Q., Q.Z., K.Z., C.T., Y.W., R.K., K.M.B., Z.X., S.C., S.G.); and Department of Pharmacology, Hebei United University, Tangshan, China (Y.Q.).
authors.forename: Shouwen
authors.initials: S
authors.lastname: Chen
authors.affiliation: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Baylor Scott & White Health, Central Texas Veterans Health Care System, Temple (Y.Q., Q.Z., K.Z., C.T., Y.W., R.K., K.M.B., Z.X., S.C., S.G.); and Department of Pharmacology, Hebei United University, Tangshan, China (Y.Q.). sguo@medicine.tamhsc.edu.
authors.forename: Shaodong
authors.initials: S
authors.lastname: Guo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental; D058065:Diabetic Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D047468:Immunoprecipitation; D007333:Insulin Resistance / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D018995:Myosin Heavy Chains / Q000096:biosynthesis / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D016277:Ventricular Function, Left / Q000502:physiology*
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C551613:Myh7 protein, mouse; D012313:RNA; D018995:Myosin Heavy Chains
keywords: Forkhead transcription factors; diabetic cardiomyopathies; insulin receptor substrate-1; insulin receptor substrate-2; insulin resistance