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

Abstract

RATIONALE:

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(-/-)).

METHODS AND 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: Hideto Mishina, Kazuhiro Watanabe, Shun Tamaru, Yosuke Watanabe, Daisuke Fujioka, Soichiro Takahashi, Koji Suzuki, Takamitsu Nakamura, Jun-Ei Obata, Kenichi Kawabata, Yasunori Yokota, Osamu Inoue, Makoto Murakami, Kohji Hanasaki, Kiyotaka Kugiyama
• Journal: Circulation research (Circ Res) Vol. 114 Issue 3 Pg. 493-504 (Jan 31 2014) ISSN: 1524-4571 [Electronic] United States
• PMID: 24305469 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Phospholipase A2

Topics

• Animals
• Genetic Predisposition to Disease (genetics)
• Heart Rupture (genetics, mortality, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Infarction (genetics, mortality, pathology)
• Receptors, Phospholipase A2 (deficiency, genetics)
• Survival Rate (trends)
• Wound Healing (genetics)