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-b (TGF-b) activation and plasmin in the proteolytic cleavage level caused by the interaction between latent TGF-b 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.

Histone acetylation is essential for ANG‐II‐induced IGF‐IIR gene expression in H9c2 cardiomyoblast cells and pathologically hypertensive rat heart

“…IGF-IIR up-regulation in patient heart has been previously linked with cardiac infarction and fibrosis (Chang et al, 2008;Chu et al, 2008). To determine whether pathologically hypertrophic stimulus may increase the IGF-IIR gene expression at the cellular level, we cultured the H9c2 cardiomyoblast cell line and neonatal cardiomyocytes and treated them with various pathological stimulators including TNF-a, LPS, ANGII, ISO, and inomycin to detect the IGF-IIR transcript using RT-PCR.…”

“…Our previous studies showed a significant association of IGF-IIR over expression with myocardial infarction and myocardial scars (Chang et al, 2008;Chu et al, 2008). Results from specifically activated IGF-IIR signaling through either inhibition of the IGF-I receptor (IGF-IR) activity by IGF-IR siRNA and AG1024 (a chemical kinase inhibitor for IGF-IR) or using Leu27IGF-II analog, reveal that IGF-IIR activated by IGF-II binding acted like a G protein-coupled receptor to activate PKC-a/CaMKII and calcineurin by association with Gaq, leading to pathological hypertrophy and mitochondriadependent cell apoptosis in cardiomyocytes (Chen et al, 2009;Chu et al, 2009a,b).…”

“…Results from specifically activated IGF-IIR signaling through either inhibition of the IGF-I receptor (IGF-IR) activity by IGF-IR siRNA and AG1024 (a chemical kinase inhibitor for IGF-IR) or using Leu27IGF-II analog, reveal that IGF-IIR activated by IGF-II binding acted like a G protein-coupled receptor to activate PKC-a/CaMKII and calcineurin by association with Gaq, leading to pathological hypertrophy and mitochondriadependent cell apoptosis in cardiomyocytes (Chen et al, 2009;Chu et al, 2009a,b). Additionally, IGF-IIR signaling activation causes the unbalance of matrix metallopeptidase 9 (MMP-9)/ tissue inhibitor of metalloproteinase 2 (TIMP-2) expression and increased plasminogen activator (PAs) expression (Chang et al, 2008), resulting in the development of myocardial remodeling. Based on those findings, suppression of the IGF-IIR gene expression and its signaling may contribute to the prevention of pathological hypertrophy, myocardial remodeling, cardiomyocyte apoptosis, and heart failure progression retardation.…”

MicroRNA-486 Alleviates Hypoxia-Induced Damage in H9c2 Cells by Targeting NDRG2 to Inactivate JNK/C-Jun and NF-κB Signaling Pathways

“…Hypoxia can induce transformation of phenotype of H9c2 cells; and myocardial cell migration and invasion are involved in the development of myocardial fibrosis because matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9 are important factors not only on regulation of migration and invasion but also on fibrosis [15,16]. Therefore, we detected migration and invasion of H9c2 cells induced by hypoxia.…”

Alpinate Oxyphyllae Fructus (Alpinia Oxyphylla Miq) Extracts Inhibit Angiotensin-II Induced Cardiac Apoptosis in H9c2 Cardiomyoblast Cells

“…23) Insulin-like growth factor II (IGF-II) also contributes by stimulating neonatal rat ventricular myocyte or H9c2 cell hypertrophy, apoptosis and remodeling. [24][25][26][27] Our previous study found that Ang II appeared to evoke IGF-II and IGF-IIR through the ERK and the JNK signaling pathway respectively, and further to activate cardiac cell apoptosis via calcineurin dependent pathways, 28) ultimately causing heart failure.…”