Lack of Phospholipase A2 Receptor Increases Susceptibility to Cardiac Rupture After Myocardial Infarction

Rationale: Recent evidence indicates that the biological effects of secretory phospholipase A(2) (sPLA(2)) cannot be fully explained by its catalytic activity. A cell surface receptor for sPLA(2) (PLA(2) receptor 1 [PLA(2)R]) and its high-affinity ligands (including sPLA(2)-IB, sPLA(2)-IIE, and sPLA(2)-X) are expressed in the infarcted myocardium. Objective: This study asked whether PLA(2)R might play a pathogenic role in myocardial infarction (MI) using mice lacking PLA(2)R (PLA(2)R(-/-)). Methods and Results: MI was induced by permanent ligation of the left coronary artery. PLA(2)R(-/-) mice exhibited higher rates of cardiac rupture after MI compared with PLA(2)R wild-type (PLA(2)R(+/+)) mice (46% versus 21%, respectively; P=0.015). PLA(2)R(-/-) mice had a 31% decrease in collagen content and a 45% decrease in the number of -smooth muscle actin-positive fibroblasts in the infarcted region compared with PLA(2)R(+/+) mice. PLA(2)R was primarily found in myofibroblasts in the infarcted region. PLA(2)R(-/-) myofibroblasts were impaired in collagen-dependent migration, proliferation, and activation of focal adhesion kinase in response to sPLA(2)-IB. Binding of sPLA(2)-IB to PLA(2)R promoted migration and proliferation of myofibroblasts through functional interaction with integrin 1, independent of the catalytic activity of sPLA(2)-IB. In rescue experiments, the injection of PLA(2)R(+/+) myofibroblasts into the infarcted myocardium prevented post-MI cardiac rupture and reversed the decrease in collagen content in the infarcted region in PLA(2)R(-/-) mice. Conclusions: PLA(2)R 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 1-mediated migratory and proliferative responses of PLA(2)R(-/-) myofibroblasts.