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1 Division of Cardiology, Armed Force Taichung General Hospital, Taichung, Taiwan, ROC2 Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, ROC3 Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan, ROC4 Trauma and Emergency Center, China Medical University Hospital, Taichung 404, Taiwan, ROC5 Post-Baccalaureate School of Chinese Medicine, China Medical University, Taichung 404, Taiwan, ROC6 Department of Pediatrics, Medical Research and Medical Genetics, China Medical University, Taichung, Taiwan, ROC7 Division of Gastroenterology, Department of Internal Medicine, Armed Force, Taichung General Hospital, Taichung, Taiwan, ROC8 Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan, ROC9 Graduate Institute of Chinese Medical Science10 Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan, ROC11 Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan, ROC
(Correspondence should be addressed to C-H Chu who is now at Graduate Institute of Basic Medical Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC; Email: s210001{at}smail.csmu.edu.tw)
* *W-J Wu, C-Y Huang and C-H Chu contributed equally to this work
The IGF-II/mannose 6-phosphate receptor (IGF2R) function in extracellular 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 ECM 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 the 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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