title: Lack of phospholipase A2 receptor increases susceptibility to cardiac rupture after myocardial infarction.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  This study asked whether PLA2R might play a pathogenic role in myocardial infarction (MI) using mice lacking PLA2R (PLA2R(-/-)).
  
  
  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% 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.
  
  
  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.
authors.affiliation: From the Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, Chuo, Yamanashi, Japan (H.M., K.W., S.T., Y.W., D.F., S.T., K.S., T.N., J.O., K.K., K.K.); Shionogi Research Laboratories, Shionogi & Co Ltd, Osaka, Japan (Y.Y., K.H.); Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan (O.I.); and Lipid Metabolism Project, the Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (M.M.).
authors.forename: Hideto
authors.initials: H
authors.lastname: Mishina
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Shun
authors.initials: S
authors.lastname: Tamaru
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fujioka
authors.forename: Soichiro
authors.initials: S
authors.lastname: Takahashi
authors.forename: Koji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Jun-Ei
authors.initials: JE
authors.lastname: Obata
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kawabata
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Yokota
authors.forename: Osamu
authors.initials: O
authors.lastname: Inoue
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
authors.forename: Kohji
authors.initials: K
authors.lastname: Hanasaki
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kugiyama
mesh_terms: D000818:Animals; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006341:Heart Rupture / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D054507:Receptors, Phospholipase A2 / Q000172:deficiency* / Q000235:genetics; D015996:Survival Rate / Q000639:trends; D014945:Wound Healing / Q000235:genetics
chemical_list: D054507:Receptors, Phospholipase A2
keywords: collagen; heart rupture; myofibroblasts; receptors, phospholipase A2