Involvement of phosphoinositide 3-kinase gamma in angiogenesis and healing of experimental myocardial infarction in mice

Mauro Siragusa, Rajesh Katare, Marco Meloni, Federico Damilano, Emilio Hirsch, Costanza Emanueli, Paolo Madeddu

Research output: Contribution to journalArticle (Academic Journal)peer-review

69 Citations (Scopus)

Abstract

RATIONALE: Phosphoinositide 3-kinase (PI3K)gamma is expressed in hematopoietic cells, endothelial cells (ECs), and cardiomyocytes and regulates different cellular functions relevant to inflammation, tissue remodeling and cicatrization. Recently, PI3Kgamma inhibitors have been indicated for the treatment of chronic inflammatory/autoimmune diseases and atherosclerosis.

OBJECTIVE: We aimed to determine PI3Kgamma contribution to the angiogenic capacity of ECs and the effect of PI3Kgamma inhibition on healing of myocardial infarction (MI).

METHODS AND RESULTS: Human umbilical ECs were treated with a selective PI3Kgamma inhibitor, AS605240, or a pan-phosphoinositide 3-kinases inhibitor, LY294002. Both inhibitory treatments and small interfering RNA-mediated PI3Kgamma knockdown strongly impaired ECs angiogenic capacity, because of suppression of the PI3K/Akt and mitogen-activated protein kinase pathways. Constitutive activation of Akt rescued the angiogenic defect. Reparative angiogenesis was studied in vivo in a model of MI. AS605240 did not affect MI-induced PI3Kgamma upregulation, whereas it suppressed Akt activation and downstream signaling. AS605240 strongly reduced inflammation, enhanced cardiomyocyte apoptosis, and impaired survival and proliferation of ECs in peri-infarct zone, which resulted in defective reparative neovascularization. As a consequence, AS605240-treated MI hearts showed increased infarct size and impaired recovery of left ventricular function. Similarly, PI3Kgamma-deficient mice showed impaired reparative neovascularization, enhanced cardiomyocyte apoptosis and marked deterioration of cardiac function following MI. Mice expressing catalytically inactive PI3Kgamma also failed to mount a proper neovascularization, although cardiac dysfunction was similar to wild-type controls.

CONCLUSIONS: PI3Kgamma expression and catalytic activity are involved at different levels in reparative neovascularization and healing of MI.

Translated title of the contributionInvolvement of Phosphoinositide 3-Kinase {gamma} in Angiogenesis and Healing of Experimental Myocardial Infarction in Mice
Original languageEnglish
Pages (from-to)757 - 768
Number of pages12
JournalCirculation Research
Volume106
Issue number4
Early online date7 Jan 2010
DOIs
Publication statusPublished - 5 Mar 2010

Bibliographical note

Publisher: Circ Res

Keywords

  • Animals
  • Apoptosis
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Chromones
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endothelial Cells
  • Humans
  • Inflammation
  • Leukocytes
  • Male
  • Mice
  • Morpholines
  • Myocardial Infarction
  • Myocardium
  • Neovascularization, Physiologic
  • Phosphatidylinositol 3-Kinases
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt
  • Quinoxalines
  • RNA Interference
  • Recovery of Function
  • Regeneration
  • Signal Transduction
  • Thiazolidinediones
  • Time Factors
  • Transfection
  • Ventricular Function, Left

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