Abstract 10348: Mice Lacking Phospholipase A2 Receptor are Susceptible to Cardiac Rupture After Myocardial Infarction through the Impaired Healing of the Infarct Region due to Myofibroblasts Dysfunction
It has long been believed that bioactive lipid mediators generated via the enzymatic activity of phospholipase A2 (PLA2) might play a role in myocardial injury after myocardial infarction (MI). Recent evidence indicates that the biological effects of PLA2s cannot be fully explained by their enzymatic activities. We have discovered a cell surface receptor for PLA2 (PLA2 receptor 1; PLA2R), the so-called M-type PLA2 receptor. PLA2R and its ligands, including PLA2-IB, IIE, V, and X, are expressed in infarcted myocardium. This study asked whether PLA2R might play a pathogenic role in cardiac rupture after MI using mice lacking PLA2R.
Methods and Results: MI was created in 11 - 12 week-old male mice by ligation of the left coronary artery. Compared with PLA2R wild-type (PLA2R WT) mice, PLA2R knockout (PLA2R KO) mice exhibited lower survival rates up to 10 days after MI (28% in KO vs. 54% in WT, p < 0.05); most of these mice died due to LV free wall cardiac rupture, as evidenced by histological examination. Immunohistochemical analysis of PLA2R WT hearts showed that PLA2R was expressed in fibroblasts expressing α-SMA and vimentin in the infarct region. PLA2R KO mice had a 31% decrease in collagen content, a 45% decrease in the number of α-SMA-positive fibroblasts and 32 - 41% decreases in the expression of pro-fibrogenic molecules; connective tissue growth factor, procollagens and TGF-β in the infarct region compared with PLA2R WT mice. The myofibroblasts cultured from PLA2R KO mice showed 33% and 27% decreases in β1 integrin-dependent migration and proliferation, respectively, in response to enzymatically-inactive PLA2-IB on collagen I-coated dishes, compared with those from PLA2R WT mice. This was associated with 40% and 25% decreases in FAK and AKT phosphorylation in PLA2R KO myofibroblasts, respectively, compared with WT myofibloblasts. In the rescue experiments, the injection of PLA2R WT myofibroblasts into the infarct myocardium prevented cardiac rupture and reversed a decrease in collagen content in the infarct region in PLA2R KO mice.
Conclusions: PLA2R KO mice had a high prevalence of cardiac rupture after MI. This might be partly explained by the impaired healing of the infarct region due to fibroblasts dysfunction.
- © 2013 by American Heart Association, Inc.