title: PI3Kγ Inhibition Protects Against Diabetic Cardiomyopathy in Mice.
abstract: OBJECTIVE
  Cardiovascular diseases, including cardiomyopathy, are the major complications in diabetes. A deeper understanding of the molecular mechanisms leading to cardiomyopathy is critical for developing novel therapies. We proposed phosphoinositide3-kinase gamma (PI3Kγ) as a molecular target against diabetic cardiomyopathy, given the role of PI3Kγ in cardiac remodeling to pressure overload. Given the availability of a pharmacological inhibitor of this molecular target GE21, we tested the validity of our hypothesis by inducing diabetes in mice with genetic ablation of PI3Kγ or knock-in for a catalytically inactive PI3Kγ.
  
  
  METHODS
  Mice were made diabetic by streptozotocin. Cardiac function was assessed by serial echocardiographic analyses, while fibrosis and inflammation were evaluated by histological analysis.
  
  
  RESULTS
  Diabetes induced cardiac dysfunction in wild-type mice. Systolic dysfunction was completely prevented, and diastolic dysfunction was partially blocked, in both PI3Kγ knock-out and kinase-dead mice. Cardiac dysfunction was similarly rescued by administration of the PI3Kγ inhibitor GE21 in a dose-dependent manner. These actions of genetic and pharmacological PI3Kγ inhibition were associated with a decrease in inflammation and fibrosis in diabetic hearts.
  
  
  CONCLUSIONS
  Our study demonstrates a fundamental role of PI3Kγ in diabetic cardiomyopathy in mice and the beneficial effect of pharmacological PI3Kγ inhibition, highlighting its potential as a promising strategy for clinical treatment of cardiac complications of diabetic patients.
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli, Isernia, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Maffei
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli, Isernia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cifelli
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli, Isernia, Italy.
authors.forename: Raimondo
authors.initials: R
authors.lastname: Carnevale
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli, Isernia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Iacobucci
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli, Isernia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pallante
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli, Isernia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Fardella
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli, Isernia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Fardella
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino, Turin, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli, Isernia, Italy; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli, Isernia, Italy; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: Daniela.carnevale@uniroma1.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Carnevale
mesh_terms: D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D004452:Echocardiography; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse
keywords: Cardiomyopathy; Diabetes mellitus; Fármacos en investigación; Investigational drugs; Miocardiopatía; Mouse; PI3Kγ protein; Proteína PI3Kγ; Ratón