IGF-II/mannose 6-phosphate receptor activation induces metalloproteinase-9 matrix activity and increases plasminogen activator expression in H9c2 cardiomyoblast cells

Mu Hsin Chang, Wei Wen Kuo, Ray Jade Chen, Ming Chin Lu, Fuu Jen Tsai, Wu Hsien Kuo, Ling Yun Chen, Wen Jun Wu, Chih Yang Huang, Chun Hsien Chu

Research output: Contribution to journalArticle

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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-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.

Original languageEnglish
Pages (from-to)65-74
Number of pages10
JournalJournal of Molecular Endocrinology
Volume41
Issue number1-2
DOIs
Publication statusPublished - Jul 2008
Externally publishedYes

Fingerprint

IGF Type 2 Receptor
Insulin-Like Growth Factor II
Plasminogen Activators
Matrix Metalloproteinase 9
Tissue Inhibitor of Metalloproteinase-2
Matrix Metalloproteinase 2
Transforming Growth Factors
Extracellular Matrix
Urokinase Plasminogen Activator Receptors
Fibrinolysin
Abdominal Aorta
Urokinase-Type Plasminogen Activator
Tissue Plasminogen Activator
Insulin-Like Growth Factor I
Hypertrophy
Small Interfering RNA
Cicatrix
Ligation
Fibrosis
Myocardial Infarction

ASJC Scopus subject areas

  • Endocrinology

Cite this

IGF-II/mannose 6-phosphate receptor activation induces metalloproteinase-9 matrix activity and increases plasminogen activator expression in H9c2 cardiomyoblast cells. / Chang, Mu Hsin; Kuo, Wei Wen; Chen, Ray Jade; Lu, Ming Chin; Tsai, Fuu Jen; Kuo, Wu Hsien; Chen, Ling Yun; Wu, Wen Jun; Huang, Chih Yang; Chu, Chun Hsien.

In: Journal of Molecular Endocrinology, Vol. 41, No. 1-2, 07.2008, p. 65-74.

Research output: Contribution to journalArticle

Chang, Mu Hsin ; Kuo, Wei Wen ; Chen, Ray Jade ; Lu, Ming Chin ; Tsai, Fuu Jen ; Kuo, Wu Hsien ; Chen, Ling Yun ; Wu, Wen Jun ; Huang, Chih Yang ; Chu, Chun Hsien. / IGF-II/mannose 6-phosphate receptor activation induces metalloproteinase-9 matrix activity and increases plasminogen activator expression in H9c2 cardiomyoblast cells. In: Journal of Molecular Endocrinology. 2008 ; Vol. 41, No. 1-2. pp. 65-74.
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T1 - IGF-II/mannose 6-phosphate receptor activation induces metalloproteinase-9 matrix activity and increases plasminogen activator expression in H9c2 cardiomyoblast cells

AU - Chang, Mu Hsin

AU - Kuo, Wei Wen

AU - Chen, Ray Jade

AU - Lu, Ming Chin

AU - Tsai, Fuu Jen

AU - Kuo, Wu Hsien

AU - Chen, Ling Yun

AU - Wu, Wen Jun

AU - Huang, Chih Yang

AU - Chu, Chun Hsien

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N2 - 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.

AB - 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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