title: Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes.
abstract: OBJECTIVE
  Diabetic cardiomyopathy is characterised by diastolic dysfunction, oxidative stress, fibrosis, apoptosis and pathological cardiomyocyte hypertrophy. Phosphoinositide 3-kinase (PI3K)(p110α) is a cardioprotective kinase, but its role in the diabetic heart is unknown. The aim of this study was to assess whether PI3K(p110α) plays a critical role in the induction of diabetic cardiomyopathy, and whether increasing PI3K(p110α) activity in the heart can prevent the development of cardiac dysfunction in a setting of diabetes.
  
  
  METHODS
  Type 1 diabetes was induced with streptozotocin in adult male cardiac-specific transgenic mice with increased PI3K(p110α) activity (constitutively active PI3K [p110α], caPI3K] or decreased PI3K(p110α) activity (dominant-negative PI3K [p110α], dnPI3K) and non-transgenic (Ntg) mice for 12 weeks. Cardiac function, histological and molecular analyses were performed.
  
  
  RESULTS
  Diabetic Ntg mice displayed diastolic dysfunction and increased cardiomyocyte size, expression of atrial and B-type natriuretic peptides (Anp, Bnp), fibrosis and apoptosis, as well as increased superoxide generation and increased protein kinase C β2 (PKCβ2), p22                   (                     phox                   ) and apoptosis signal-regulating kinase 1 (Ask1) expression. Diabetic dnPI3K mice displayed an exaggerated cardiomyopathy phenotype compared with diabetic Ntg mice. In contrast, diabetic caPI3K mice were protected against diastolic dysfunction, pathological cardiomyocyte hypertrophy, fibrosis and apoptosis. Protection in diabetic caPI3K mice was associated with attenuation of left ventricular superoxide generation, attenuated Anp, Bnp, PKCβ2, Ask1 and p22                   (                     phox                   ) expression, and elevated AKT. Further, in cardiomyocyte-like cells, increased PI3K(p110α) activity suppressed high glucose-induced superoxide generation and enhanced mitochondrial function.
  
  
  CONCLUSIONS
  These results demonstrate that reduced PI3K activity accelerates the development of diabetic cardiomyopathy, and that enhanced PI3K(p110α) activity can prevent adverse cardiac remodelling and dysfunction in a setting of diabetes.
authors.affiliation: Baker IDI Heart and Diabetes Institute, St Kilda Rd Central, Melbourne, VIC 8008, Australia. rebecca.ritchie@bakeridi.edu.au
authors.forename: R H
authors.initials: RH
authors.lastname: Ritchie
authors.forename: J E
authors.initials: JE
authors.lastname: Love
authors.forename: K
authors.initials: K
authors.lastname: Huynh
authors.forename: B C
authors.initials: BC
authors.lastname: Bernardo
authors.forename: D C
authors.initials: DC
authors.lastname: Henstridge
authors.forename: H
authors.initials: H
authors.lastname: Kiriazis
authors.forename: Y K
authors.initials: YK
authors.lastname: Tham
authors.forename: G
authors.initials: G
authors.lastname: Sapra
authors.forename: C
authors.initials: C
authors.lastname: Qin
authors.forename: N
authors.initials: N
authors.lastname: Cemerlang
authors.forename: E J H
authors.initials: EJ
authors.lastname: Boey
authors.forename: K
authors.initials: K
authors.lastname: Jandeleit-Dahm
authors.forename: X-J
authors.initials: XJ
authors.lastname: Du
authors.forename: J R
authors.initials: JR
authors.lastname: McMullen
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D058534:Class I Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000517:prevention & control*; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress; D013481:Superoxides / Q000378:metabolism*
chemical_list: D013481:Superoxides; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases