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M Chang, Department of Internal Medicine, Armed-Force, Taichung General Hospital, Division of Cardiology, Taichung, Taiwan - Republic of China
W Kuo, China Medical University, Department of Biological Science and Technology, Taichung, Taiwan - Republic of China
R Chen, China Medical University Hospital, Trauma and Emergency Center, Taichung, Taiwan - Republic of China
M Lu, China Medical University, Post-Baccalaureate School of Chinese Medicine, Taichung, Taiwan - Republic of China
F Tsai, China Medical University, Department of Pediatrics, Medical Research and Medical Genetics, Taichung, Taiwan - Republic of China
W Kuo, Department of Internal Medicine, Armed-Force, Taichung General Hospital, Division of Gastroenterology, Taichung, Tanzania, United Republic Of
L Chen, Chung Shan Medical University, Institute of Biochemistry and Biotechnology, Taichung, Taiwan - Republic of China
W Wu, Chung Shan University, Institute of Medical and Molecular Toxicology, Taichung, Taiwan - Republic of China
C Huang, Asia, Department of Health and Nutrition Biotechnology, Taichung, Taiwan - Republic of China
C Chu, Chung Shan Medical University, Institute of Biochemistry and Biotechnology, Taichung, Taiwan - Republic of China

Correspondence: Ling-Yun Chen, Email: s210001{at}smail.csmu.edu.tw

Abstract

The IGF-II/mannose 6-phosphate receptor (IGF2R) function in extra-cellular matrix (ECM) remodeling is known to occur as a result of transforming growth factor-β (TGF-β) activation and plasmin in the proteolytic cleavage level caused by the interaction between latent TGF-β and urokinase plasminogen activator receptor (uPAR), respectively. In one of our previous studies, we found IGF-II and IGF2R dose-dependently correlated with the progression of pathological hypertrophy remodeling following complete abdominal aorta ligation. However, how this IGF2R signaling pathway responds specifically to IGF-II and regulates the myocardial extra-cellular matrix remodeling process is unclear. We found that IGF2R was aberrantly expressed in myocardial infarction scars. The matrix metalloproteinase-9 (MMP-9) zymographic activity was elevated in H9c2 cardiomyoblast cells treated with IGF-II, but not IGF-I. Treatment with Leu27IGF-II, an IGF2R specifically binding IGF-II analog, resulted in significant time-dependent increases in the MMP-9, tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) and a reduction in tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) protein expression. Furthermore, IGF2R expression inhibition by siRNA blocked the IGF-II-induced MMP-9 activity. We hypothesize that after IGF-II is bound with IGF2R, the resulting signal disrupts the balance in the MMP-9/TIMP-2 expression level and increases plasminogen activator (PAs) expression involved in the development of myocardial remodeling. If so, IGF2R signaling inhibition may have potential use in the development of therapies preventing heart fibrosis progression.

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