title: IGF-II/mannose 6-phosphate receptor activation induces metalloproteinase-9 matrix activity and increases plasminogen activator expression in H9c2 cardiomyoblast cells.
abstract: 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-beta (TGF-beta) activation and plasmin in the proteolytic cleavage level caused by the interaction between latent TGF-beta 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.
authors.affiliation: Division of Cardiology, Armed Force Taichung General Hospital, Taichung, Taiwan, ROC Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, ROC.
authors.forename: Mu-Hsin
authors.initials: MH
authors.lastname: Chang
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.forename: Ray-Jade
authors.initials: RJ
authors.lastname: Chen
authors.forename: Ming-Chin
authors.initials: MC
authors.lastname: Lu
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Wu-Hsien
authors.initials: WH
authors.lastname: Kuo
authors.forename: Ling-Yun
authors.initials: LY
authors.lastname: Chen
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Wu
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.forename: Chun-Hsien
authors.initials: CH
authors.lastname: Chu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D017527:Receptor, IGF Type 2; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9