scholarly journals Upregulation of Cardiac Insulin-like Growth Factor-I Receptor by ACE Inhibition After Myocardial Infarction: Potential Role in Remodeling

2003 ◽  
Vol 51 (6) ◽  
pp. 831-839 ◽  
Author(s):  
Rachael G. Dean ◽  
Leon A. Bach ◽  
Louise M. Burrell
Keyword(s):  
Myocardial Infarction ◽  
Blood Pressure ◽  
Growth Factor ◽  
Cardiac Remodeling ◽  
Ace Inhibition ◽  
Border Zone ◽  
Positive Effects ◽  
Igf System ◽  
Igf I ◽  
Igfbp 3

This study evaluated the effects of angiotensin-converting enzyme (ACE) inhibition after myocardial infarction (MI) on cardiac remodeling and gene expression and localization of components (ligands, receptors, and binding proteins) of the cardiac insulinlike growth factor (IGF) system. After ligation of the coronary artery, rats were randomized to vehicle or ACE inhibitor (Captopril, 50 mg/kg/day) for 4 weeks. Blood pressure, cardiac remodeling, and components of the IGF system were localized in the heart using in situ hybridization (ISH) and immunohistochemistry (IHC). The average infarct size was 42%. There were regional differences in the expression of the IGF system after MI, with increased IGF-I mRNA abundance in the border (24-fold) and infarct (12-fold) and increased IGF-binding protein (IGFBP)-3 mRNA in all areas of the failing left ventricle (threefold). Captopril reduced blood pressure, attenuated cardiac remodeling, and caused a threefold increase in IGF-I receptor mRNA and protein in infarct, border zone, and viable myocardium ( p<0.01). Captopril had no effect on IGF-I mRNA but further increased IGFBP-3 mRNA and protein in the border zone, ( p<0.05). The changes in the cardiac IGF system following MI are highly localized, persist for at least 4 weeks, and can be modulated by ACE inhibition. These data suggest that the benefits of ACE inhibitors in attenuation of cardiac remodeling may be mediated in part through increased expression of the IGF-I receptor sensitizing the myocardium to the positive effects of endogenous IGF-I.

Physical capacity influences the response of insulin-like growth factor and its binding proteins to training

2002 ◽  
Vol 93 (5) ◽  
pp. 1669-1675 ◽  
Author(s):  
Lars Rosendal ◽  
Henning Langberg ◽  
Allan Flyvbjerg ◽  
Jan Frystyk ◽  
Hans Ørskov ◽  
...  
Keyword(s):  
Growth Factor ◽  
Physical Training ◽  
Binding Proteins ◽  
Insulin Like Growth Factor ◽  
Initial Training ◽  
Serum Samples ◽  
Fitness Level ◽  
Igf System ◽  
Igf I ◽  
Igfbp 3

The influence of initial training status on the response of circulating insulin-like growth factor (IGF) and its binding proteins (IGFBP) to prolonged physical training was studied in young men. It was hypothesized that highly standardized training would result in more extensive changes in the circulating IGF system in untrained subjects because of lower fitness level. Seven untrained (UT) and 12 well-trained (WT) individuals performed 11 wk of intense physical training (2–4 h daily). Fasting serum samples were analyzed for total and free IGF-I and -II, for IGFBP-1 to -4, as well as for IGFBP-3 proteolysis. Eleven weeks of physical training resulted in decreased levels of total IGF-I, free IGF-I, and IGFBP-4 in both the UT and WT groups. In the UT group, IGFBP-2 increased, IGFBP-3 decreased [from 4,255 ± 410 (baseline) to 3,896 ± 465 (SD) μg/l ( week 4); P < 0.05], and IGFBP-3 proteolysis increased [from 28 ± 8% (baseline) to 37 ± 7% ( week 4) and 39 ± 12% ( week 11); P < 0.05], whereas no significant changes were found in the WT group. In conclusion, intense physical training results in a marked influence on the IGF system and its binding proteins with generally more extensive changes seen in the untrained individuals. Also, prolonged physical training resulted in increased IGFBP-3 proteolysis in previously untrained individuals only, indicating that intense physical training affects trained and untrained individuals differently.

scholarly journals Dietary intake and the insulin-like growth factor system: effects of migration in two related populations in India and Britain with markedly different dietary intake

2005 ◽  
Vol 8 (6) ◽  
pp. 620-627 ◽  
Author(s):  
AH Heald ◽  
R Sharma ◽  
SG Anderson ◽  
A Vyas ◽  
K Siddals ◽  
...  
Keyword(s):  
Growth Factor ◽  
Dietary Intake ◽  
Total Energy ◽  
Macronutrient Intake ◽  
Fat Intake ◽  
Insulin Like Growth Factor ◽  
Igf System ◽  
Igf I ◽  
Total Fat ◽  
Igfbp 3

AbstractBackgroundThe insulin-like growth factor (IGF) system is implicated in the pathogenesis of diabetes and cardiovascular disease.ObjectiveWe report the effects of total energy intake on the IGF system in two populations with markedly different dietary macronutrient intake and cardiovascular event rate.Design, subjects and settingDietary macronutrient intake was measured in a specific Gujarati migrant community in Sandwell, UK (n = 205) compared with people still resident in the same villages of origin in India (n = 246). Fasting IGF-I, IGF-binding protein (IGFBP)-1 and IGFBP-3, insulin and glucose (0 and 2-hour) were measured.ResultsTotal energy and total fat intake were higher in UK migrants, as were IGFBP-3 and IGF-I (mean (95% confidence interval): 145.9 (138.1–153.6) vs. 100.9 (94.6–107.3) ng ml-1; F = 76.6, P < 0.001). IGFBP-1 was lower in UK migrants (29.5 (25.9–33.0) vs. 56.5 (50.6–62.5) μg l-1; F = 48.4, P < 0.001). At both sites, IGF-I correlated positively with total energy (Spearman's ρ = 0.45, P < 0.001) and total fat (ρ = 0.44, P < 0.001) as did IGFBP-3 with total energy (ρ = 0.21, P < 0.05) and fat (ρ = 0.26, P < 0.001). Conversely, in Indian Gujaratis, IGFBP-1 fell with increasing total energy (ρ = -0.27, P < 0.001) and fat intake (ρ = -0.26, P < 0.01) but not in UK Gujaratis. Multiple linear regression modelling showed that increasing quartiles of fat intake were associated with higher IGF-I (β = 0.42, P = 0.007) independent of age, body mass index, plasma insulin, fatty acids and 2-hour glucose.ConclusionIn these genetically similar groups, migration to the UK and adoption of a different diet is associated with marked changes in the IGF system, suggesting that environmental factors profoundly modulate serum concentrations and actions of IGFs.

Effect of a high maternal dietary intake during mid-gestation on components of the utero-placental insulin-like growth factor (IGF) system in adolescent sheep with retarded placental development

Reproduction ◽  
2000 ◽  
pp. 407-416 ◽  
Author(s):  
TS Gadd ◽  
RP Aitken ◽  
JM Wallace ◽  
DC Wathes
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Maternal Nutrition ◽  
Limit Of Detection ◽  
Receptor Expression ◽  
Insulin Like Growth Factor ◽  
Placental Development ◽  
Igf System ◽  
Igf I ◽  
Igfbp 3

The aim of the present study was to investigate the effects of administering a high plane diet during early to mid-gestation on the uterine and placental insulin-like growth factor (IGF) system and on systemic IGF-I concentrations in pregnant adolescent ewes with restricted placental growth. Embryos recovered from superovulated ewes inseminated by a single sire were transferred in singleton to the uterus of adolescent recipients. After transfer ewes were offered a high (H) or moderate (M) amount of a complete diet calculated to promote rapid or normal maternal growth rates, respectively. Five ewes from each group were switched from either M to H or H to M diets at day 52 of gestation. Maternal and fetal blood samples and placental tissues were collected from all animals at day 104. Ewes on the high plane diet from mid-gestation (HH, MH groups) had restricted placental mass (P < 0.01) and tended to have smaller fetuses. This was associated with increased maternal plasma IGF-I concentrations (P < 0.001). The pattern of expression of components of the IGF system in the uterus and placenta was studied by in situ hybridization. IGF-I mRNA concentrations were below the limit of detection. IGF-II mRNA expression was high in the fetal mesoderm and present in maternal stroma, but was not influenced by nutritional treatment. In contrast, IGF binding protein 1 (IGFBP-1) mRNA expression was higher (P < 0.05) and IGFBP-3 mRNA expression was lower (P < 0.05) in the endometrial glands of ewes in HH and MH groups. In the fetal trophoblast, IGFBP-3 mRNA expression was higher in the MH group. Type 1 IGF receptor expression was increased (P < 0. 01) in the luminal epithelium of the HM group and IGFBP-2 mRNA expression was highest in the placentome capsule of ewes in the HH group. Together, these results indicate that reprogramming of the uterine and placental IGF axis by maternal nutrition could contribute to placental growth retardation in growing adolescent sheep.

scholarly journals Regulation of proliferation of prostate epithelial cells by 1,25-dihydroxyvitamin D3 is accompanied by an increase in insulin-like growth factor binding protein-3

2001 ◽  
Vol 170 (3) ◽  
pp. 609-618 ◽  
Author(s):  
CC Sprenger ◽  
A Peterson ◽  
R Lance ◽  
JL Ware ◽  
RH Drivdahl ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Human Prostate ◽  
Dihydroxyvitamin D3 ◽  
Prostate Epithelial Cell ◽  
Igf System ◽  
Prostate Epithelial Cells ◽  
Igf I ◽  
Igfbp 3

The biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown to regulate the proliferation of human prostate epithelial cell lines. Since the insulin-like growth factor (IGF) system is involved in the transformation process of epithelial cells, the following study was undertaken to determine if the IGF system, in particular IGF binding protein-3 (IGFBP-3), is altered by 1,25-(OH)2D3 in normal prostate epithelial cells as part of a mechanism for inhibition of transformation. Two cell systems were used in this study: (1) primary cultures of benign human prostate epithelial cells (PECs) and (2) an SV40-T immortalized prostate epithelial cell line (P153) that is non-tumorigenic. 1,25-(OH)2D3 was added to parallel sets of PECs and P153 cells in addition to the presence or absence of IGF-I or des(1-3)IGF-I. Treatment with 1,25-(OH)2D3 resulted in significant growth inhibition of both PECs and P153 cells. Furthermore, 1,25-(OH)2D3 inhibited IGF-induced proliferation, but this was partially reversed by high concentrations of IGF-I. Western ligand blots of condition media demonstrated a significant increase in IGFBP-3; likewise Northern blots demonstrated an increase in mRNA for IGFBP-3. Proliferation assays using an antibody designed to block the IGF-independent effects of IGFBP-3 failed to reverse the inhibitory effect of 1,25-(OH)2D3. Thus, IGFBP-3 acts in an IGF-dependent manner to inhibit cell growth of benign prostate epithelial cells.

scholarly journals Connective Tissue Growth Factor and Cardiac Fibrosis after Myocardial Infarction

2005 ◽  
Vol 53 (10) ◽  
pp. 1245-1256 ◽  
Author(s):  
Rachael G. Dean ◽  
Leanne C. Balding ◽  
Riccardo Candido ◽  
Wendy C. Burns ◽  
Zemin Cao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Ace Inhibition ◽  
Left Ventricular ◽  
Tissue Growth ◽  
Viable Myocardium ◽  
Border Zone ◽  
Collagen Protein

The temporal and spatial expression of transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF) was assessed in the left ventricle of a myocardial infarction (MI) model of injury with and without angiotensin-converting enzyme (ACE) inhibition. Coronary artery ligated rats were killed 1, 3, 7, 28, and 180 days after MI. TGF-β1, CTGF, and procollagen α1(I) mRNA were localized by in situ hybridization, and TGF-β1 and CTGF protein levels by immunohistochemistry. Collagen protein was measured using picrosirius red staining. In a separate group, rats were treated for 6 months with an ACE inhibitor. There were temporal and regional differences in the expression of TGF-β1, CTGF, and collagen after MI. Procollagen α1(I) mRNA expression increased in the border zone and scar peaking 1 week after MI, whereas collagen protein increased in all areas of the heart over the 180 days. Expression of TGF-β1 mRNA and protein showed major increases in the border zone and scar peaking 1 week after MI. The major increases in CTGF mRNA and protein occurred in the viable myocardium at 180 days after MI. Long-term ACE inhibition reduced left ventricular mass and decreased fibrosis in the viable myocardium, but had no effect on cardiac TGF-β1 or CTGF. TGF-β1 is involved in the initial, acute phase of inflammation and repair after MI, whereas CTGF is involved in the ongoing fibrosis of the heart. The antifibrotic benefits of captopril are not mediated through a reduction in CTGF.

scholarly journals HaCaT human keratinocytes express IGF-II, IGFBP-6, and an acid-activated protease with activity against IGFBP-6

1999 ◽  
Vol 276 (3) ◽  
pp. E536-E542 ◽  
Author(s):  
Joe A. Marinaro ◽  
Elke C. Hendrich ◽  
Kerri S. Leeding ◽  
Leon A. Bach
Keyword(s):  
Growth Factor ◽  
Cathepsin D ◽  
Human Keratinocytes ◽  
Hacat Keratinocytes ◽  
Igf System ◽  
Igf I ◽  
Igf Binding ◽  
Mrna And Protein Expression ◽  
Igf Binding Protein ◽  
Igfbp 3

The insulin-like growth factor (IGF) system plays an important role in skin. HaCaT human keratinocytes proliferate in response to IGFs and synthesize IGF-binding protein-3 (IGFBP-3). Recently, IGFBP-6 was also identified by NH2-terminal sequencing, but it has not been identified by Western ligand blotting. In the present study, IGFBP-6 was detected in HaCaT-conditioned medium by use of immunoblotting and Western ligand blotting with125I-labeled IGF-II. Proteolytic activity against IGFBPs, an important mechanism for regulation of their activity, was then studied. An acid-activated, cathepsin D-like protease that cleaved both IGFBP-6 and IGFBP-3 was detected. Although proteolysis did not substantially reduce the size of immunoreactive IGFBP-6, it greatly reduced the ability of IGFBP-6 to bind125I-IGF-II as determined by Western ligand blotting and solution assay. HaCaT keratinocytes do not express IGF-I mRNA, but IGF-II mRNA and protein expression was detected. These observations suggest the possibility of an autocrine IGF-II loop that is regulated by the relative expression of IGF-II, IGFBP-3, and IGFBP-6, and IGFBP proteases in these keratinocytes, although demonstration of this loop requires further study.

scholarly journals Alterations in insulin-like growth factor binding protein-3 proteolysis and complex formation in the arthritic joint

2000 ◽  
Vol 165 (3) ◽  
pp. 545-556 ◽  
Author(s):  
EJ Whellams ◽  
LA Maile ◽  
JK Fernihough ◽  
ME Billingham ◽  
JM Holly
Keyword(s):  
Growth Factor ◽  
Synovial Fluid ◽  
Complex Formation ◽  
Binding Protein ◽  
Disease Process ◽  
Ternary Complexes ◽  
Insulin Like Growth Factor ◽  
Igf System ◽  
Igf I ◽  
Igfbp 3

Increased concentrations of insulin-like growth factor (IGF) system components have previously been observed in rheumatoid arthritis (RA) and osteoarthritis (OA); however, disruption of the IGF axis and the implications for the disease process remain largely unaddressed. This study was undertaken to characterise the IGF binding protein (IGFBP)-3 proteolysis and complex formation systems in synovial fluid and to investigate changes in these systems in arthritic disease, and their impact on the availability of IGF. Western blotting or autoradiography of SDS gels was used to visualise IGFBP-3 or its proteolysis. IGF-I and IGFBP-3 concentrations were determined by radioimmunoassays and acid-labile subunit (ALS) was measured by ELISA. A shift in distribution of IGFBP-3 and IGF-I in RA and OA synovial fluids (RASynF, OASynF) and an associated increase in ALS suggested the presence of 150 kDa ternary complexes. IGFBP-3 proteolysis was decreased in RASynF and OASynF, but was apparent in size-fractionated fluid and resembled serum activity. The presence of serum-like inhibitors of IGFBP-3 proteolysis in RASynF was also demonstrated by the ability of this fluid, and 150 kDa fractions from its size fractionation, to inhibit IGFBP-3 proteolysis in the other synovial fluid. A marked disruption in the IGF system was observed, as considerably more IGF-I was retained in ternary complexes. We also classified the IGFBP-3 proteolysis system in synovial fluid and found it to be disturbed in RASynF and OASynF. These changes may be caused by an increased flux of circulatory proteins into synovial fluid, resulting from an inflammation-induced increase in vascular permeability. The net result in RA and OA would be a decrease in IGF availability in arthritic joints, and therefore loss of a potential anabolic stimulus. This disruption to the IGF axis would influence disease progression in RA and OA.

Gene Expression of Insulin-Like Growth Factor Binding Proteins (IGFBP-2 and IGFBP-3) in Childhood Acute Myeloblastic Leukemia. Intr. by Herbert Sayer.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4292-4292
Author(s):  
Kristin Dawczynski ◽  
Bernd Gruhn ◽  
Nadine Pfaffendorf ◽  
Wittig Susan ◽  
Astrit Voigt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Growth Factor ◽  
Leukemic Cells ◽  
Healthy Children ◽  
Insulin Like Growth Factor ◽  
Igf System ◽  
Igf I ◽  
Median Expression ◽  
Igfbp 3

Abstract Insulin-like growth factor (IGF) system plays an important role in regulating cellular proliferation. Alterations to the Insulin-like growth factor system have been reported for different tumors. They are of particular interest in the search for new prognostic and therapeutic approaches to cancer treatment. This study aimed to investigate the expression of IGFBP-2, IGFBP-3, IGF-I and IGF-II genes in leukemic cells from children with previously untreated acute myeloblastic leukemia (AML).The expression of IGF-I and IGF-II genes as well as IGFBP-2 and IGFBP-3 genes were measured using TaqMan real-time PCR in 50 children (mean age 10.8±4.8 years). All four genes were expressed with a great variability. RNA samples were extracted from leukemic cells enriched by Ficoll-Hypaque density gradient separation of bone marrow or peripheral blood mononuclear cells (MNC). MNC samples from peripheral blood and bone marrow of healthy children were used as controls. The median expression of IGFBP-2 was 25 times higher in AML cells than in peripheral MNC (p<0.001) and 10 times higher in bone marrow of healthy children (p<0.01). Increased IGFBP-2 gene expression at time of diagnosis was associated with a poor prognosis and a shortened survival time. Leukemic cells of patients who remained in continuous complete remission during the follow up showed a significant decreased IGFBP-2 gene expression at time of diagnosis compared to patients who suffered from relapse (p=0.05).On the other hand, AML cells showed a significantly lower IGFBP-3 gene expression than controls. The median expression of IGFBP-3 was 30 times lower in AML cells than in peripheral MNC (p<0.001) and 20 times lower than in bone marrow of healthy children (p<0.001). No significant difference could be found in IGF-I and IGF-II expression between leukemic and normal cells. Leukemic cells from children with previously untreated AML express components of IGF system. Especially IGFBP-2 seems to play an important role. By this mechanism, IGFBP-2 promotes their own growth in an autocrine, paracrine or endocrine manner. Whether these components will be useful as prognostic factors in stratification of AML treatment in children needs to be evaluated.

Cardiac-specific ablation of theSTAT3gene in the subacute phase of myocardial infarction exacerbated cardiac remodeling

2015 ◽  
Vol 309 (3) ◽  
pp. H471-H480 ◽  
Author(s):  
Daichi Enomoto ◽  
Masanori Obana ◽  
Akimitsu Miyawaki ◽  
Makiko Maeda ◽  
Hiroyuki Nakayama ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Biological Significance ◽  
Weight Ratio ◽  
Fluorescence Analysis ◽  
Border Zone ◽  
Intrinsic Activity ◽  
Heart Weight ◽  
Subacute Phase

STAT3 is a cardioprotective molecule against acute myocardial injury; however, recent studies have suggested that chronic STAT3 activation in genetically modified mice was detrimental after myocardial infarction (MI). In the present study, we assessed the biological significance of STAT3 activity in subacute MI using tamoxifen (TM)-inducible cardiac-specific STAT3 knockout (STAT3 iCKO) mice. After coronary ligation, STAT3 was rapidly activated in hearts, and its activation was sustained to the subacute phase. To make clear the pathophysiological roles of STAT3 activation specifically in subacute MI, MI was generated in STAT3 iCKO mice followed by TM treatment for 14 consecutive days beginning from day 11 after MI, which ablated the STAT3 gene in the subacute phase. Intriguingly, mortality was increased by TM treatment in STAT3 iCKO mice, accompanied by an increased heart weight-to-body weight ratio. Masson's trichrome staining demonstrated that cardiac fibrosis was dramatically exacerbated in STAT3 iCKO mice 24 days after MI (fibrotic circumference: 58.3 ± 6.7% in iCKO mice and 40.8 ± 9.3% in control mice), concomitant with increased expressions of fibrosis-related gene transcripts, including matrix metalloproteinase 9, procollagen 1, and procollagen 3. Echocardiography clarified that cardiac function was deteriorated in STAT3 iCKO mice (fractional shortening: 20.6 ± 4.1% in iCKO mice and 29.1 ± 6.0% in control mice). Dihydroethidium fluorescence analysis revealed that superoxide production was increased in STAT3 iCKO mice. Moreover, immunohistochemical analyses revealed that capillary density was decreased in STAT3 iCKO mice. Finally, STAT3 deletion in subacute MI evoked severe cardiac hypertrophy in the border zone. In conclusion, the intrinsic activity of STAT3 in the myocardium confers the resistance to cardiac remodeling in subacute MI.

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