Lack of Phospholipase A2 Receptor Increases Susceptibility to Cardiac Rupture after Myocardial Infarction
Rationale: Recent evidence indicates that the biological effects of secretory phospholipase A2s (sPLA2) cannot be fully explained by their catalytic activities. A cell surface receptor for sPLA2 (PLA2 receptor 1 [PLA2R]) and its high affinity ligands (including sPLA2-IB, -IIE, and -X) are expressed in the infarcted myocardium.
Objective: This study asked whether PLA2R might play a pathogenic role in myocardial infarction (MI), using mice lacking PLA2R (PLA2R-/-).
Methods and Results: MI was induced by permanent ligation of the left coronary artery. PLA2R-/- mice exhibited higher rates of cardiac rupture after MI compared with PLA2R wild-type (PLA2R+/+) mice (46% vs. 21%, respectively, P = 0.015). PLA2R-/- mice had a 31% decrease in collagen content and a 45% decrease in the number of α-SMA-positive fibroblasts in the infarcted region compared with PLA2R+/+ mice. PLA2R was primarily found in myofibroblasts in the infarcted region. PLA2R-/- myofibroblasts were impaired in collagen-dependent migration, proliferation and activation of focal adhesion kinase in response to sPLA2-IB. Binding of sPLA2-IB to PLA2R promoted migration and proliferation of myofibroblasts through functional interaction with integrin β1 independent of the catalytic activity of sPLA2-IB. In rescue experiments, the injection of PLA2R+/+ myofibroblasts into the infarcted myocardium prevented post-MI cardiac rupture and reversed the decrease in collagen content in the infarcted region in PLA2R-/- mice.
Conclusions: PLA2R deficiency increased the susceptibility to post-MI cardiac rupture through impaired healing of the infarcted region. This might be partly explained by a reduction in integrin β1-mediated migratory and proliferative responses of PLA2R-/- myofibroblasts.
- Received August 5, 2013.
- Revision received December 2, 2013.
- Accepted December 4, 2013.