Abstract 16253: Distinctive Functions of PI3Kβ in Endothelial Cells and Cardiomyocytes in Response to Myocardial Infarction: Complications for Targeting PI3Kβ in Myocardial Infarction Treatment
Introduction: Differential cellular responses and signaling cascades contribute to cardiac remodeling after myocardial infarction (MI). The phosphoinositide 3-kinase (PI3K)/Akt pathway regulates multiple pathways in post-MI remodeling.
Hypothesis: The PI3K isoform, p110β, in endothelial cells and cardiomyocytes mediates distinct responses to MI.
Methods: Mice with kinase-dead p110β expressed specifically in cardiomyocytes (p110β-αMHC) or endothelial cells (p110β-Tie2) were generated; p110β-Flx was used as littermate controls. Intraperitoneal injection of Tamoxifen (2mg/mouse for 5 days) was given to 9-week-old p110β-Tie2 to activate kinase-dead p110β expression. Sham- or MI-operation on 12-week-old mice and 7-day post-operated echocardiography were performed in a blinded fashion. Triphenyl tetrazolium chloride (TTC), CD31, and wheat germ agglutinin (WGA) staining were performed to examine the infarct size, vascular density, and hypertrophy on 7-day post-operated mice. Signaling pathways were assessed by Western blotting.
Results: Successful inactivation of p110β was confirmed by PCR. Loss of p110β activity in endothelial cells resulted in increased survival rate (24/24 vs. 33/40, p<0.05), decreased infarct size by 11.42% (p<0.05), and higher vascular density in peri-infarct area, resulting in preservation of systolic function (EF 46.41±2.7 vs. 33.78±2.2%, p<0.01) after MI in comparison to controls. Increased phosphorylation of the pro-survival Akt (2.7- to 4.7-fold) and Erk1/2 (1.7- to 2.6-fold) was detected in infarct, peri-infarct, and non-infarct areas from p110β-Tie2. In contrast, inactivation of p110β in cardiomyocytes increased MI-related mortality (7/22), infarct size by 8.88%, and hypertrophy in non-infarct area with reduced angiogenesis, leading to deterioration of systolic function (EF 20.33±2.3%, p<0.01), compared to controls.
Conclusions: Inhibition of endothelial p110β improves cardiac performance after MI, possibly through feedback mechanisms leading to activation of pAkt by other PI3K isoforms. Conversely, cardiomyocyte p110β is required to maintain cardiac function following MI. These results indicate the importance of cell-type specific of PI3Kβ signaling in the response to heart disease.
Author Disclosures: X. Chen: None. P. Zhabyeyev: None. J. DesAulniers: None. X. Wang: None. F. Wang: None. A.G. Murray: None. Z. Kassiri: None. B. Vanhaesebroeck: None. G.Y. Oudit: None.
- © 2016 by American Heart Association, Inc.