Lack of Phospholipase A ₂ Receptor Increases Susceptibility to Cardiac Rupture After Myocardial Infarction

Abstract

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 α-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 β1, 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 β1–mediated migratory and proliferative responses of PLA 2 R –/– myofibroblasts.

Macrophage-Derived mir-155-Containing Exosomes Suppress Fibroblast Proliferation and Promote Fibroblast Inflammation during Cardiac Injury

“…In the early phase of myocardial infarction, cardiac fibroblast proliferation prevents cardiac rupture, improves the survival rate, and promotes cardiac repair. 38,39 Growing evidence shows that expansion of the inflammatory response results in cardiomyocyte death, deterioration in remodeling, and dysfunction after myocardial infarction through the release of reactive oxygen species, matrix metalloproteinase, and pro-inflammatory cytokines, 40 In this study, we demonstrate that a mir-155 deficiency increased fibroblast proliferation and collagen synthesis and reduced the inflammatory response, which would likely decrease the incidence of cardiac rupture in the early stage of myocardial infarction and improve cardiac function. Importantly, the transfusion of macrophage-derived exosomes to mir-155 À/À mice recovered mir-155 expression in the heart and increased the incidence of cardiac rupture ( Figure 6).…”

A new era of secreted phospholipase A2

“…Pla2r1 Ϫ / Ϫ mice show lower infl ammation after LPS challenge through some unknown mechanism ( 150 ). In a model of allergen-induced asthma, the lungs of Pla2r1 Ϫ / Ϫ mice show greater infi ltration of immune cells and higher levels of eicosanoids and Th2 cytokines, accompanied by greater levels of sPLA 2 -IB and -X proteins, than those of wild-type mice ( 151 ), providing the fi rst in vivo evidence that PLA2R1 serves as a clearance receptor for these sP-LA 2 s. In a model of myocardial infarction, Pla2r1 Ϫ / Ϫ mice exhibit higher rates of cardiac rupture, with impaired collagen-dependent migration, growth, and activation of myofi broblasts ( 152 ). Mechanistically, binding of sPLA 2 -IB to PLA2R1 augments the migration and growth of myofibroblasts, and thereby wound healing, through functional interaction with integrin, supporting the signaling role of PLA2R1.…”

Akt-dependent Girdin phosphorylation regulates repair processes after acute myocardial infarction

“…Our data showed that the increased incidence of cardiac rupture observed in Girdin SA/SA mice might be attributable to impaired recruitment of myofibroblasts to the infarcted area. In fact, prior studies have revealed that adaptive fibrosis in the infarcted area prevents cardiac rupture [28,29]. For example, Hofmann et al reported that the osteogenesis imperfecta mouse model, which lacks procollagen-α2(I) expression, exhibits increased mortality due to higher incidence of cardiac rupture, and deficiency of collagen type I leads to a myocardial wound-healing defect [30].…”