title: PI3Kα is essential for the recovery from Cre/tamoxifen cardiotoxicity and in myocardial insulin signalling but is not required for normal myocardial contractility in the adult heart.
abstract: OBJECTIVE
  Genetic mouse models have yielded conflicting conclusions about the role of PI3Kα in heart physiology: specifically, the question of whether PI3Kα has a direct role in regulating myocardial contractility. This has led to concerns that PI3K inhibitors currently in clinical trials for cancer may potentiate cardiotoxicity. Here we seek to clarify the role of PI3Kα in normal heart physiology and investigate changes in related signalling pathways.
  
  
  RESULTS
  Targeted deletion of PI3Kα and PI3Kβ in the heart with a tamoxifen-dependent Cre recombinase transgene caused transient heart dysfunction in all genotypes, but only PI3Kα deletion prevented functional recovery. Reduction in tamoxifen dosing allowed for maintained gene deletion without any cardiomyopathy, possibly through activation of survival signalling through the related ERK pathway. Similarly, mice with PI3Kα deletion induced by constitutively active Cre recombinase had normal heart function. Insulin-mediated activation of Akt, a marker of PI3Kα activity, was impaired with increased ERK1/2 activation in PI3Kα mutant hearts. Pharmacological inhibition of PI3Kα with BYL-719 also caused impaired insulin signalling in murine and human cardiomyocytes as well as in vivo in mice, with increased fasting blood glucose levels, but did not affect myocardial contractility as determined by echocardiography and invasive pressure-volume loop analysis.
  
  
  CONCLUSIONS
  Our results show that PI3Kα does not directly regulate myocardial contractility, but is required for recovery from tamoxifen/Cre toxicity. The important role for PI3Kα in insulin signalling and recovery from tamoxifen/Cre toxicity justifies caution when using PI3Kα inhibitors in combination with other cardiovascular comorbidities and cardiotoxic compounds in cancer patients.
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Brent A
authors.initials: BA
authors.lastname: McLean
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada Division of Cardiology, Department of Medicine, University of Alberta, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.
authors.forename: Pavel
authors.initials: P
authors.lastname: Zhabyeyev
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada Division of Cardiology, Department of Medicine, University of Alberta, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada Division of Cardiology, Department of Medicine, University of Alberta, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.
authors.forename: Nirmal
authors.initials: N
authors.lastname: Parajuli
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada Division of Cardiology, Department of Medicine, University of Alberta, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: DesAulniers
authors.affiliation: Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Allan G
authors.initials: AG
authors.lastname: Murray
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.affiliation: UCL Cancer Institute, University College London, London, UK.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada Division of Cardiology, Department of Medicine, University of Alberta, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada gavin.oudit@ualberta.ca.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D005838:Genotype; D006331:Heart Diseases / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism*; D019426:Integrases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D007328:Insulin; D019426:Integrases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013629:Tamoxifen; C546639:Pik3ca protein, mouse; C045073:Cre recombinase
keywords: Cardiomyocytes; Contractility; Cre recombinase; Insulin; PI3K