Lack of phospholipase A2 receptor increases susceptibility to cardiac rupture after myocardial infarction.

Abstract

Recent evidence indicates that the biological effects of secretory phospholipase A2 (sPLA2) cannot be fully explained by its catalytic activity. A cell surface receptor for sPLA2 (PLA2 receptor 1 [PLA2R]) and its high-affinity ligands (including sPLA2-IB, sPLA2-IIE, and sPLA2-X) are expressed in the infarcted myocardium. This study asked whether PLA2R might play a pathogenic role in myocardial infarction (MI) using mice lacking PLA2R (PLA2R(-/-)). 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% versus 21%, respectively; P=0.015). PLA2R(-/-) mice had a 31% decrease in collagen content and a 45% decrease in the number of α-smooth muscle actin-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. 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.