Myeloid cell-derived LRG attenuates adverse cardiac remodelling after myocardial infarction.

Abstract

AIMS:

Leucine-rich α2-glycoprotein (LRG) is considered as a biomarker of the clinical activities of chronic inflammatory diseases, including heart failure. However, its pathophysiological roles in cardiac remodelling after myocardial infarction (MI) remain to be clarified. In this study, we have addressed functional roles of LRG in cardiac remodelling after MI.

METHODS AND RESULTS:

MI was generated by ligating the left coronary artery in mice. Real-time reverse transcription (RT)-PCR and immunoblot analyses revealed that the expressions of LRG transcript and protein were up-regulated in post-infarct myocardium. LRG protein was produced by heart-infiltrating myeloid cells, such as macrophages and neutrophils. To elucidate functional roles of LRG in cardiac remodelling, we generated MI in wild-type (WT) and LRG-deficient (LRG(-/-)) mice and found that LRG gene ablation aggravated myocardial fibrosis with cardiac dysfunction after MI. Immunohistochemical analyses with anti-CD31 antibody revealed that capillary density decreased at border zone in LRG(-/-) mice compared with WT mice. Consistently, the expression of apelin receptor was reduced in LRG(-/-) mice, implying that the impaired angiogenic activity is associated with adverse cardiac remodelling in LRG(-/-) mice. Moreover, LRG gene ablation suppressed the activation of smad1/5/8, a pro-angiogenic signalling pathway. Finally, the transplantation of WT bone marrow cells into LRG(-/-) mice attenuated cardiac fibrosis with functional improvement after MI, accompanied by restoration of capillary density compared with the bone marrow transplantation from LRG(-/-) mice.

CONCLUSION:

LRG, produced by heart-infiltrating myeloid cells, suppresses adverse cardiac remodelling after MI as a novel cardioprotective factor. LRG signalling could be a therapeutic target against cardiovascular diseases.

• Authors: Shohei Kumagai, Hiroyuki Nakayama, Minoru Fujimoto, Hiromi Honda, Satoshi Serada, Hatsue Ishibashi-Ueda, Atsushi Kasai, Masanori Obana, Yasushi Sakata, Yoshiki Sawa, Yasushi Fujio, Tetsuji Naka
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 109 Issue 2 Pg. 272-82 (Feb 01 2016) ISSN: 1755-3245 [Electronic] England
• PMID: 26678356 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: [email protected].

Chemical References

• Glycoproteins
• LRG1 protein, mouse

Topics

• Animals
• Coronary Vessels (metabolism, pathology)
• Fibrosis (metabolism)
• Glycoproteins (genetics)
• Heart (physiopathology)
• Heart Failure (pathology)
• Mice, Knockout
• Myocardial Infarction (metabolism)
• Neovascularization, Physiologic (physiology)
• Ventricular Remodeling (physiology)