Author(s): Chang, MH (Chang, Mu-Hsin); Kuo, WW (Kuo, Wei-Wen); Chen, RJ (Chen, Ray- Jade); Lu, MC (Lu, Ming-Chin); Tsai, FJ (Tsai, Fuu-Jen); Kuo, WH (Kuo, Wu-Hsien); Chen, LY (Chen, Ling-Yun); Wu, WJ (Wu, Wen-Jun); Huang, CY (Huang, Chih-Yang); Chu, CH (Chu, Chun-Hsien)
Title: IGF-II/mannose 6-phosphate receptor activation induces metalloproteinase-9 matrix activity and increases plasminogen activator expression in H9c2 cardiomyoblast cells Source: JOURNAL OF MOLECULAR ENDOCRINOLOGY, 41 (1-2): 65-74 JUL-AUG 2008 Language: English
Document Type: Article
KeyWords Plus: GROWTH-FACTOR-II; HEART-FAILURE; MYOCARDIAL-INFARCTION;
TGF-BETA; INHIBITION; RAT; BINDING; SYSTEM; DYSFUNCTION; UROKINASE
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-13 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 Leu271GF-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.
Addresses: [Chang, Mu-Hsin] Armed Force Taichung Gen Hosp, Div Cardiol, Taichung, Taiwan; [Chang, Mu-Hsin; Wu, Wen-Jun] Chung Shan Med Univ, Inst Med & Mol Toxicol, Taichung, Taiwan; [Kuo, Wei-Wen] China Med Univ, Dept Biol Sci & Technol, Taichung 404, Taiwan; [Chen, Ray-Jade] China Med Univ Hosp, Trauma & Emergency Ctr, Taichung 404, Taiwan; [Lu, Ming-Chin] China Med Univ, Post Baccalaureate Sch Chinese Med, Taichung 404, Taiwan; [Tsai, Fuu-Jen] China Med Univ, Dept Pediat Med Res & Med Genet, Taichung 404, Taiwan; [Kuo, Wu-Hsien] Taichung Gen Hosp, Dept Internal Med, Div Gastroenterol,
Taichung, Taiwan; [Chen, Ling-Yun; Chu, Chun-Hsien] Chung Shan Med Univ, Inst Biochem &
Biotechnol, Taichung 402, Taiwan; [Huang, Chih-Yang] China Med Univ, Grad Inst Chinese Med Sci, Taichung 404, Taiwan; [Huang, Chih-Yang; Chu, Chun-Hsien] China Med Univ, Inst Basic Med Sci, Taichung 404, Taiwan; [Huang, Chih-Yang] Asia Univ, Dept Hlth & Nutr Biotechnol, Taichung 413, Taiwan
Reprint Address: Chu, CH, China Med Univ, Grad Inst Basic Med Sci, 91 Hsueh Shih Rd, Taichung 404, Taiwan.
E-mail Address: [email protected]
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Cited Reference Count: 29 Times Cited: 3
Publisher: SOC ENDOCRINOLOGY
Publisher Address: 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND
ISSN: 0952-5041
DOI: 10.1677/JME-08-0051
29-char Source Abbrev.: J MOLECULAR ENDOCRINOL ISO Source Abbrev.: J. Mol. Endocrinol.
Source Item Page Count: 10
Subject Category: Endocrinology & Metabolism ISI Document Delivery No.: 341XW
