title: Pharmacologic inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) promotes infarct resorption and prevents adverse cardiac remodeling after myocardial infarction in mice.
abstract: BACKGROUND
  Phosphoinositide 3-kinase gamma is upregulated in the heart during acute myocardial infarction (AMI) potentially contributing to the development and maintenance of heart failure.
  
  
  METHODS
  CD-1 male mice were randomly assigned to pharmacologic inhibition of phosphoinositide 3-kinase gamma using AS-605240 (10 mg/kg/day intraperitoneally) or vehicle (NaCl 0.9% + DMSO 25% solution) for 14 days after experimental AMI induced by surgical coronary artery ligation. Echocardiography was performed at baseline and 1, 7, 14, and 28 days after surgery to measure left ventricular dimensions and function. Infarct size was also measured at weekly intervals to evaluate for infarct resorption.
  
  
  RESULTS
  When compared with vehicle-treated mice over the 4-week period, animals treated with AS-605240 showed a smaller increase in left ventricular cavitary dimensions, a smaller decrease in left ventricular systolic function (P < 0.05), and a significant increase in posterior wall diastolic and systolic thickness reflective of compensatory hypertrophy (P < 0.05). Initial infarct size (measured at 24 hours) was not different comparing AS-605240 (29% ± 4%) and vehicle-treated mice (31% ± 1%, P = nonsignificant). At 4 weeks after AMI, infarct size was significantly smaller in the AS-605240-treated mice (14% ± 2%) compared with vehicle-treated mice (28% ± 3%, P < 0.001), reflecting greater infarct resorption.
  
  
  CONCLUSIONS
  Phosphoinositide 3-kinase gamma inhibition with AS-605240 after AMI leads to enhanced infarct resorption, greater compensatory hypertrophy of the nonischemic myocardium, and more favorable cardiac remodeling and function.
authors.affiliation: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Ignacio M
authors.initials: IM
authors.lastname: Seropian
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.forename: Stefano
authors.initials: S
authors.lastname: Toldo
authors.forename: Jessica
authors.initials: J
authors.lastname: Harrington
authors.forename: Lisa
authors.initials: L
authors.lastname: Smithson
authors.forename: Ramzi
authors.initials: R
authors.lastname: Ockaili
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mezzaroma
authors.forename: Federico
authors.initials: F
authors.lastname: Damilano
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Van Tassell
mesh_terms: D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000494:pharmacology* / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D045162:Thiazolidinediones; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse