Abstract 15101: Pellino1 is Required to Preserve Myocardial Function and Promote Neovascularization in the Infarcted Myocardium
Introduction: Acute myocardial infarction is a leading cause of death among patients with cardiovascular disease. We have recently shown that Pellino-1 (Peli1) gene therapy can induce angiogenesis and improve heart functions in the infarcted myocardium making it an attractive therapeutic target. In the present study, we aimed to explore the functional role of Peli1 in inducing neovascularization after myocardial infarction (MI) using Peli1 global knockout mice (Peli1KO).
Methods: Wild-type (Peli1fl/fl) and Peli1KO ( Peli1-/-) mice were subjected to either permanent ligation of the left anterior descending coronary artery (LAD) or sham surgery (S). Left ventricular risk area post-MI at different time points were collected for gel shift analysis (NFκB), protein analysis and immunohistochemistry after echocardiographic analysis.
Results: Peli1 deficiency (Peli1KO) exacerbated myocardial dysfunction 60 days after MI compared to WT with reduced ejection fraction [30±2.5 vs. 41±2.6% (n=8); p<0.0001] and fractional shortening [14±1.3 vs. 20±1.3% (n=8); p<0.0001] measured by echocardiogram. Capillary density was found to be significantly lower in Peli1KO-MI mice [1814±143 vs. 2284±217 counts/mm2 (n=4-5); p<0.0076] compared to WT-MI mice. We also evaluated phospho-MAPKAPK2 (2.6 fold) and NFκB and found it to be significantly downregulated in the Peli1KO-MI group compared to the WT-MI. Peli1KO mice also demonstrated increased myocardial oxidative stress markers 4-hydroxynonenal and 3’-nitrotyrosine (1.4 fold) along with myocardial fibrosis [32±5.8 vs. 23±3.8% (n=5-6); p<0.05] in the Peli1KO-MI group as compared to WT-MI. We have also generated transgenic mice with cardiomyocyte-specific Peli1 expression (AMPEL1) and subjected them to MI. In contrast to Peli1KO mice, the AMPEL1-MI group mice showed increased vessel density [2917±219 vs. 2005±206 counts/mm2 (n=5-8);p<0.0001] along with reduced myocardial fibrosis [23±3.4 vs. 47±6.1% (n=5-7); p<0.0001] compared to the WT-MI group.
Conclusion: Our data suggest that deletion of Peli1 impairs angiogenesis and exacerbates myocardial dysfunction whereas overexpression of Peli1 enhances angiogenesis and reduces myocardial fibrosis post-MI.
Author Disclosures: M. Thirunavukkarasu: None. B. Oriowo: None. V. Selvaraju: None. M. Joshi: None. L. Tapias: None. V. Coca-Soliz: None. I. Saad: None. J.A. Sanchez: None. J. Palestey: None. S. Yee: None. N. Maulik: None.
- © 2016 by American Heart Association, Inc.