Pharmacologic inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) promotes infarct resorption and prevents adverse cardiac remodeling after myocardial infarction in mice.
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.
Seropian
Ignacio M
IM
VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.
Abbate
Antonio
A
Toldo
Stefano
S
Harrington
Jessica
J
Smithson
Lisa
L
Ockaili
Ramzi
R
Mezzaroma
Eleonora
E
Damilano
Federico
F
Hirsch
Emilio
E
Van Tassell
Benjamin W
BW
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
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