Mechano-Growth Factor Reduces Loss of Cardiac Function in Acute Myocardial Infarction

Carpenter, V. A.; Matthews, Kenneth G.; Devlin, Gerard; Stuart, Selwyn; Jensen, Joergen L.; Conaglen, John V.; Jeanplong, Ferenc; Goldspink, Paul H.; Yang, Shiyu; Goldspink, Geoffrey; Bass, J. J.; McMahon, Christopher D.

doi:10.1016/j.hlc.2007.04.013

Cited by 62 publications

(52 citation statements)

References 32 publications

(20 reference statements)

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“…We have defined that the IGF-1Ec transcript is expressed both at the mRNA and protein level. This particular IGF-1 transcript has been associated with regeneration mechanisms of skeletal muscle and myocardial cells (20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have investigated the expression patterns of these IGF-1 transcripts in skeletal muscle (17)(18)(19), and there is growing interest vis-à-vis the potential role of MGF expression in skeletal and cardiac muscle regeneration and hypertrophy after exerciseinduced skeletal muscle damage (20) and myocardial infarction (21,22). In addition, we have previously reported preliminary data on the expression of IGF-1 isoforms in endometriosis at mRNA level (23).…”

Section: Subjectsmentioning

confidence: 99%

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Insulinlike Growth Factor-1Ec (MGF) Expression in Eutopic and Ectopic Endometrium: Characterization of the MGF E-Peptide Actions In Vitro

Milingos

Philippou

Armakolas

et al. 2010

Mol Med

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The transcription of the insulinlike growth factor 1 (igf-1) gene generates three mRNA isoforms, namely IGF-1Ea, IGF-1Eb and IGF1Ec (or MGF [mechano growth factor]). Herein, we analyzed the expression of IGF-1 isoforms in eutopic and ectopic endometrium (red lesions and endometriotic cysts) of women with endometriosis, and we characterized the actions of a synthetic MGF E-peptide on KLE cells. Our data documented that all three igf-1 gene transcripts are expressed in the stromal cells of the eutopic and ectopic endometrium; however, endometriotic cysts contained significantly lower IGF-1 isoform expression, both at the mRNA and protein level, as was shown using semiquantitative PCR and immunohistochemical methods. In addition, the glandular cells of the eutopic endometrium did not express any of the IGF-1 isoforms; however, the glandular cells of the ectopic endometrium (red lesions) did express the IGF-1Ec at mRNA and protein level. Furthermore, synthetic MGF E-peptide, which comprised the last 24 amino acids of the MGF, stimulated the growth of the KLE cells. Experimental silencing of the type 1 IGF receptor (IGF-1R) and insulin receptor expression of KLE cells (siRNA knock-out methods) did not alter the mitogenic action of the synthetic MGF E-peptide, revealing that MGF E-peptide stimulates the growth of KLE cells via an IGF-1R-independent and insulin receptor-independent mechanism. These data suggest that the IGF-1Ec transcript might generate, apart from mature IGF-1 peptide, another posttranslational bioactive product that may have an important role in endometriosis pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

Insulinlike Growth Factor-1Ec (MGF) Expression in Eutopic and Ectopic Endometrium: Characterization of the MGF E-Peptide Actions In Vitro

Milingos

Philippou

Armakolas

et al. 2010

Mol Med

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“…Although, by the general consensus, IGF-I is thought to exert its biological actions predominantly through mature peptide, differential biological activities have been reported for the different IGF-I isoforms (propeptides), or for their E-peptides, exogenously administrated or overexpressed in various in vivo (28,29,36,(132)(133)(134) and in vitro models (20,27,(31)(32)(33)135,136), implying that there are peptides other than the IGF-I ligand that also possess bioactivity and, thus, both common and unique or complementary pathways exist for the IGF-I isoforms to promote biological effects (31,36).…”

Section: Igf-i Peptides Actions and Signalingmentioning

confidence: 99%

The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

Philippou

Maridaki

Pneumaticos

et al. 2014

Mol Med

100

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The insulinlike growth factor-I (IGF-I) is an important factor which regulates a variety of cellular responses in multiple biological systems. The IGF1 gene comprises a highly conserved sequence and contains six exons, which give rise to heterogeneous mRNA transcripts by a combination of multiple transcription initiation sites and alternative splicing. These multiple transcripts code for different precursor IGF-I polypeptides, namely the IGF-IEa, IGF-IEb and IGF-IEc isoforms in humans, which also undergo posttranslational modifications, such as proteolytic processing and glycosylation. IGF-I actions are mediated through its binding to several cell-membrane receptors and the IGF-I domain responsible for the receptor binding is the bioactive mature IGF-I peptide, which is derived after the posttranslational cleavage of the pro-IGF-I isoforms and the removal of their carboxy-terminal E-peptides (that is, the Ea, Eb and Ec). Interestingly, differential biological activities have been reported for the different IGF-I isoforms, or for their E-peptides, implying that IGF-I peptides other than the IGF-I ligand also possess bioactivity and, thus, both common and unique or complementary pathways exist for the IGF-I isoforms to promote biological effects. The multiple peptides derived from IGF-I and the differential expression of its various transcripts in different conditions and pathologies appear to be compatible with the distinct cellular responses observed to the different IGF-I peptides and with the concept of a complex and possibly isoform-specific IGF-I bioactivity. This concept is discussed in the present review, in the context of the broad range of modifications that this growth factor undergoes which might regulate its mechanism(s) of action.

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“…Interestingly, the IGF-1 Eb peptide, also called mechano-growth factor (MGF), has been shown to improve cardiac function and preserve blood supply to heart muscle (Carpenter et al, 2008).…”

Section: Chapter 5 Investigating Whether the Igfbp Domain Of Crim1 Camentioning

confidence: 99%

“…Full length CRIM1-myc and all CRIM1-myc-tagged deletion constructs were co-transfected in HEK293 cells with IGF-1Eb-HA, due to its suggested role in the heart (Carpenter et al, 2008). In each case, IGF-1 Eb-HA was immunoprecipitated with CRIM1, but at varying levels.…”

Section: Crim1 Binds Igf-1 Via Its Igfbp-like Domain and Crrs 3-6mentioning

confidence: 99%

Analysis of the Role of Crim1 in Heart Development

Iyer¹

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To overcome the societal and financial burden of cardiovascular disease, a thorough understanding of the molecular and cellular programmes governing cardiac and coronary vascular development is vital. Cre-mediated genetic tracing in various models has provided valuable insight into cell-lineage contribution and inductive cues required for cardiac morphogenesis. Using mouse models, we have identified the transmembrane protein Cysteine-Rich Transmembrane BMP Regulator-1 (Crim1) as an essential protein for numerous aspects of heart development. The presence of six Cysteine-Rich Repeats (CRRs) in Crim1 render it to be a versatile molecule -these have been shown to bind a wide range of growth factors when Crim1 is co-expressed in the same cell as the growth factor . The main objective of this thesis is to examine the role that Crim1 plays both temporally and spatially during heart development, and how it functions in tandem with other factors to ensure the progression of this critical process.Crim1 is strongly expressed in the proepicardium (PE), epicardium, coronary vascular smooth muscle cells and, to a weaker extent, in coronary endothelial cells .Interestingly, Crim1 mutant homozygotes die perinatally on a C57BL6 background . Loss of Crim1 function leads to a reduced ventricular size and hypoplastic ventricular compact myocardium, and abnormal epicardial morphology including blebbing and a loss of the regular, cobblestone appearance of the epicardium. Furthermore, epicardium-restricted deletion of Crim1 resulted in increased epicardial epithelial-to-mesenchymal transition (EMT) and invasion of the myocardium, while primary epicardial cells lacking Crim1 displayed an increased migration.Growth factors like TGFs are known to promote epicardial EMT; however, we observed a paradoxical reduction in epicardial TGF signalling in Crim1 mutant embryos. Interestingly, there appeared to be an accumulation of -catenin, a cell-adhesion molecule present at cadherindependent junctional complexes in epithelial cells, at epicardial cell-cell junctions, suggesting an interaction with Crim1 to promote stabilization of these junctions. There was also an increase in the level of phospho-ERK1/2 in the ventricular compact myocardium of mutants, though phospho-AKT levels remained unchanged. This indicates a cell-autonomous role for Crim1 in controlling epicardial migration, EMT and invasion, and a potential paracrine role in regulating myocardial development, likely through regulation of epicardium derived factors.Another notable defect observed in the absence of Crim1 is that the coronary vasculature also appears to be malformed. We found a reduction in coronary vascular endothelial cell endowment in We also sought to understand the role of Crim1 in growth factor modulation in endothelial cells in vivo. There was a decrease in phospho-SMAD1/5 activity in endothelial cells from ventricles of Crim1Δflox/Δflox homozygotes, suggesting a dysregulation of TGFβ/BMP signalling in these cells, confirming our in vitro data. However, t...

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Mechano-Growth Factor Reduces Loss of Cardiac Function in Acute Myocardial Infarction

Cited by 62 publications

References 32 publications

Insulinlike Growth Factor-1Ec (MGF) Expression in Eutopic and Ectopic Endometrium: Characterization of the MGF E-Peptide Actions In Vitro

Insulinlike Growth Factor-1Ec (MGF) Expression in Eutopic and Ectopic Endometrium: Characterization of the MGF E-Peptide Actions In Vitro

The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

Analysis of the Role of Crim1 in Heart Development

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