title: Dual loss of PI3Kα and PI3Kγ signaling leads to an age-dependent cardiomyopathy.
abstract: Phosphatidylinositide 3-kinase (PI3K) signaling plays a critical role in maintaining normal cardiac structure and function. PI3Kα and PI3Kγ are the dominant cardiac isoforms and have both adaptive and maladaptive roles in heart disease. Broad spectrum PI3K inhibitors are emerging as potential new chemotherapeutic agents which may have deleterious long-term effects on the heart. We created a double mutant (PI3KDM) model by crossing p110γ(-/-) (PI3KγKO) with cardiac-specific PI3KαDN mice and studied cardiac structure and function at 1-year of age. Pressure-volume loop analysis and echocardiographic assessment showed PI3KDM mice developed marked impairment in systolic function while the wildtype, PI3KαDN, and PI3KγKO mice maintained normal systolic and diastolic function at 1-year of age. The PI3KDM hearts displayed increased expression of disease markers, increased myocardial fibrosis and matrix metalloproteinase (MMP) activity, depolymerization of intracellular F-actin, loss of phospho(threonine-308)-Akt, and normalization of phospho-Erk1/2 signaling. Dual loss of PI3Kα and PI3Kγ isoforms results in an age-dependent cardiomyopathy implying that long-term exposure to pan-PI3K inhibitors may lead to severe cardiotoxicity.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
authors.forename: Pavel
authors.initials: P
authors.lastname: Zhabyeyev
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
authors.forename: Brent
authors.initials: B
authors.lastname: McLean
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada; Department of Physiology, University of Alberta, Edmonton, Canada.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
authors.forename: Tharmarajan
authors.initials: T
authors.lastname: Ramprasath
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada; Department of Physiology, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. Electronic address: gavin.oudit@ualberta.ca.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000375:Aging; D000818:Animals; D002306:Cardiac Volume; D009202:Cardiomyopathies / Q000201:enzymology* / Q000235:genetics; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics; D006352:Heart Ventricles / Q000201:enzymology / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020257:Ventricular Remodeling
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase
keywords: Aging; Cardiomyopathy; Phosphatidylinositol-4,5-bisphosphate 3-kinase; Signaling