Abstract 9905: Myeloid Cell Derived Leucine Rich α2 Glycoprotein Attenuates Adverse Cardiac Remodeling After Myocardial Infarction
Background: Leucine rich α2 glycoprotein (LRG), a member of the leucine-rich repeat family, was isolated from human plasma. Recently, LRG has been identified as a novel serum biomarker for various inflammatory diseases. It was also reported that serum LRG concentrations was strongly correlated with B-type natriuretic peptide in patients with heart failure. However, its pathophysiological roles in hearts after myocardial infarction (MI) remain to be elucidated.
Objective: To determine the functional roles of LRG in cardiac remodeling after MI.
Methods and Results: Murine MI was generated by ligating the left coronary artery. The expression of LRG was increased in hearts after MI. Immunofluorescence microscopic and flow cytometric analyses revealed that LRG was mainly produced by CD11b-positive myeloid cells in post-infarct myocardium. To elucidate pathophysiological roles of LRG in heart, we generated MI in wild-type (WT) and LRG-knockout (KO) mice. At day 14 after MI, cardiac fibrosis and dysfunction were aggravated in KO mice compared to WT mice (fibrotic area/ LV area: WT: 34.1 ± 7.2%, KO: 46.5 ± 12.8% n=10-16, p<0.01) (fractional shortening: WT: 34.8±7.1%, KO: 24.3±7.0%, n=6-9, p<0.01). Immunohistochemical analysis demonstrated that CD31-positive vessel density decreased at border zone in KO mice compared to WT mice 14 days after MI (vessel density: WT: 2740±190/mm2, KO: 2183±293/mm2 n=10-16, p<0.01). We explored the mechanism of LRG-mediated angiogenesis in post-infarct myocardium, and found that the activation of smad1/5/8, a pro-angiogenic signaling pathway, was attenuated in KO mice. Accompanied by impaired angiogenesis, cardiomyocytes apoptosis was increased in KO mice compared to WT mice at subacute phase after MI. Finally, bone marrow chimera experiments showed that bone marrow cells-derived LRG rescued adverse cardiac remodeling in KO mice, accompanied by restoration of capillary density.
Conclusion: LRG was mainly produced by heart-infiltrated myeloid cells, and suppressed adverse cardiac remodeling after MI through enhanced angiogenesis. In this study, LRG was defined as a novel cardioprotective factor. Thus, LRG could be not only a serum biomarker but also a therapeutic target in cardiovascular diseases.
Author Disclosures: S. Kumagai: None. H. Nakayama: None. M. Fujimoto: None. H. Honda: None. S. Serada: None. A. Kasai: None. M. Obana: None. Y. Sakata: None. Y. Sawa: None. T. Naka: None. Y. Fujio: Research Grant; Modest; DAIICHI SANKYO COMPANY, LIMITED, Takeda Pharmaceutical Company Limited, Pfizer Inc.. Research Grant; Significant; Bristol-Myers Squibb Company.
- © 2015 by American Heart Association, Inc.