Shohei Kumagai1, Hiroyuki Nakayama1, Minoru Fujimoto2, Hiromi Honda2, Satoshi Serada2, Hatsue Ishibashi-Ueda3, Atsushi Kasai4, Masanori Obana1, Yasushi Sakata5, Yoshiki Sawa6, Yasushi Fujio7, Tetsuji Naka8. 1. Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmacological Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, Japan. 2. Laboratory of Immune Signals, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, Japan. 3. Department of Pathology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan. 4. Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan. 5. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. 6. Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. 7. Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmacological Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, Japan tnaka@nibio.go.jp fujio@phs.osaka-u.ac.jp. 8. Laboratory of Immune Signals, National Institute of Biomedical Innovation, 7-6-8 Saitoasagi, Ibaraki, Osaka, Japan tnaka@nibio.go.jp fujio@phs.osaka-u.ac.jp.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Chenghao Liu; Melissa Hui Yen Teo; Sharon Li Ting Pek; Xiaoting Wu; Mei Ling Leong; Hui Min Tay; Han Wei Hou; Christiane Ruedl; Stephen E Moss; John Greenwood; Subramaniam Tavintharan; Wanjin Hong; Xiaomeng Wang Journal: Diabetes Date: 2020-09-04 Impact factor: 9.461