Microsoft Word - 302319R2_PAP_12_4_13

Subject codes: [108] Other myocardial biology [145] Genetically altered mice, [151] Ischemic biology-basic studies In November 2013, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.6 days. ABSTRACT Rationale: Recent evidence indicates that the biological effects of secretory phospholipase A 2 s (sPLA 2) cannot be fully explained by their catalytic activities. A cell surface receptor for sPLA 2 (PLA 2 receptor 1 [PLA 2 R]) and its high affinity ligands (including sPLA 2-IB,-IIE and-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% vs. 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-SMA-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. Nonstandard Abbreviations and Acronyms: PLA 2 Phospholipases A 2 sPLA 2 secretory PLA 2 PLA 2 R phospholipase A 2 receptor 1 CRDs carbohydrate-recognition domains LV left ventricle MI myocardial infarction LVDd LV end-diastolic diameter LVDs LV end-systolic diameter LVFS LV fractional shortening ELISA enzyme-linked immunosorbent assay TGF transforming growth factor CTGF connective tissue growth factor MMP matrix metalloproteinase TUNEL Terminal deoxynucleotidyl transferase dUTP nick end …