Growth Hormone and Insulin-like Growth Factor 1: New Endocrine Therapies in Cardiology?

The hormones growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play a dominant role in whole body growth and metabolism. This is reflected in the use of human GH (hGH) in GH-deficient children to stimulate growth and in GH-deficient adults to reduce visceral fat mass. Recent data suggest that hGH may improve cardiac function in patients with heart failure, so there is current interest in methods to raise GH-IGF levels, including the testing of agents that release GH from the pituitary, administering IGF-1, and most recently, long-acting formulations of hGH. It is hoped that this ongoing integration of cardiology and endocrinology will uncover the pathophysiology of some cardiovascular diseases and yield new treatments based on the hormones of the GH axis. (Trends Cardiovasc Med 1997;7:264-268). ? 1997, Elsevier Science Inc.     

Immunolocalization of Transforming Growth Factor-α and Epidermal Growth Factor Receptor in the Rat Gastroduodenal Area

The maintenance of gastrointestinal epitheliumintegrity requires a fine balance between proliferationand differentiation as well as protection againstgastric acid secretion. Transforming growthfactor- (TGF-) regulates these functions bybinding to epidermal growth factor receptor (EGF-R).This study was designed to identify the localization ofTGF- and EGF-R in the rat gastroduodenal region. In the stomach, the surface and gastric pitcells showed staining for TGF- antibodies in thecytoplasm and basolateral and apical membranes.TGF- and EGF-R were observed in the supranuclearregion of the cells lining the gland. In the duodenum,the enterocytes coexpressed both TGF- and EGF-Rin the supranuclear area. The EGF-R was also observed inthe apical membrane. Brunner's glands were positive for both TGF- and EGF-R antibodies. Ourresults demonstrate the coexpression of TGF- andEGF-R in the rat gastroduodenal area, which suggests afunctional role for them in the establishment and maintenance of the epithelialrenewal.     

Age-Related Changes of Transforming Growth Factor β1 in Japanese Children

BackgroundTransforming growth factor β1 (TGFβ1) is an important factor in immunomodulation. The expression of TGFβ1 has been shown to be influenced by the C-509 T polymorphism in the TGFβ1 gene. We investigated age-related changes of plasma TGFβ1 levels in a birth-cohort study. In addition, the genotypes of the C-509 T polymorphism were investigated in allergic and non-allergic subjects.MethodsSixty-four neonates who met the following criteria were enrolled in this cohort study: 1) full-term vaginally delivery; 2) underwent DNA polymorphism analysis; and 3) questionnaire forms were filled out by parents at 0, 6 and 14 months of age. The umbilical cord blood at 0 months and peripheral blood at 6, and 14 months were collected. Plasma TGFβ1 levels were measured at 0, 6 and 14 months of age. Genomic DNA was extracted from their umbilical cord blood. The genotype of the subjects was examined for the presence of C- 509 T.ResultsThe plasma TGFβ1 level at 6 months was the highest of the 3 measurements (at 0, 6, and 14 months of age). The TGFβ1 levels at 14 months in allergic subjects were significantly higher than those in non-allergic subjects (p = 0.03). All subjects with bronchial asthma (n = 3) had the TT genotype of the C-509 T polymorphism.ConclusionsThe plasma TGFβ1 levels change with age. In addition, TGFβ1 may play a role in the pathogenesis of bronchial asthma.     

Insulin Like Growth Factor—1 and Insulin—Like Growth Factor Binding Proteins: Their Possible Roles in Both Maintaining Normal Retinal Vascular Function and in Promoting Retinal Pathology

Reviews in Endocrine and Metabolic Disorders -     

Expression of Transforming Growth Factor β1 in Bronchial Biopsies in Asthma and COPD

The role of transforming growth factor β₁ (TGF β₁) in airway remodeling in asthma and chronic obstructive pulmonary disease (COPD) has not been fully described. To evaluate the possible pathogenetic role of TGF β₁ in asthma and COPD, immunohistochemical expression of TGF β₁ was described in bronchial biopsies from patients with asthma and COPD compared with healthy individuals. Twelve subjects with asthma, 13 subjects with COPD, and 10 healthy individuals enrolled in the study. Bronchial biopsies were stained with hematoxylin and eosin and anti‐TGF β₁ antibody. As a result, immunoreactive TGF β₁ was mainly localized in association with connective tissue in all groups. The staining intensity was not statistically different among the groups in bronchial epithelium, whereas it was significantly higher in the group of asthma in the submucosa. Because there is evidence showing a significant increase of staining intensity in the submucosa from asthmatics but not from subjects with COPD, we may conclude that TGF β₁ may play a significant role in pathogenesis of asthma but not in COPD.     

Vascular Endothelial Growth Factor Attenuates Nω-Nitro-L-Arginine Methyl Ester-Induced Preeclampsia-Like Manifestations in Rats

Objectives. To verify the hypothesis that vascular endothelial growth factor (VEGF) attenuates Nω-Nitro-L-arginine Methyl Ester (L-NAME)-induced preeclampsia-like manifestations in rats. Study design. Forty pregnant Wistar rats were randomly divided into four groups: control, preeclampsia model, VEGF treatment, and VEGF prophylactic. On day 5 of gestation, L-NAME was injected subcutaneously in rats of the preeclampsia model, VEGF treatment, and VEGF prophylactic groups. VEGF was given after the occurrence of hypertension and proteinuria in the VEGF treatment group and from day 5 in the VEGF prophylactic group. Blood pressure was monitored and urine protein was assayed. Blood platelet was counted, and serum nitric oxide metabolites, endothelin-1, 6-keto-PGF-1α, and TXB2 were determined. Results. Blood pressure increased significantly on day 8 of gestation in the preeclampsia model and VEGF treatment groups compared with control (p < 0.05 for both) and remained elevated through the pregnancy in the preeclampsia model group. Blood pressure was significantly decreased after the administration of VEGF in the VEGF treatment group (p < 0.05). There was no significant difference in blood pressure between the VEGF prophylactic group and control (p > 0.05). Urine protein, platelet count, serum nitric oxide metabolites, endothelin-1, 6-keto-PGF-1α, and TXB2 were significantly different between control and the preeclampsia model group (p < 0.05), but not between control and the VEGF treatment or VEGF prophylactic groups (p > 0.05 for all). Conclusion. VEGF attenuates L-NAME-induced preeclampsia-like manifestations in rats, suggesting the important role of VEGF in preeclampsia and providing a potential strategy for the prevention and treatment of preeclampsia.     

Interleukin-4 Modulation of Platelet-Derived Growth Factor–Induced Smooth Muscle Cell Urokinase Plasminogen Activator

Platelet-derived growth factor (PDGF) stimulates smooth muscle cell (SMC) migration owing to stimulation of SMC tissue plasminogen activator (t-PA) production. In this study we examined the effects of the T-cell lymphokine interleukin-4 (IL-4) on PDGF induction of human aortic SMC antigen levels of urokinase-type plasminogen activator (u-PA) and those of plasminogen activator inhibitor-1 (PAI-1), the endogenous inhibitor of t-PA and u-PA, measured by enzyme-linked immunosorbent assays (ELISAs). u-PA antigen levels from human aortic SMC incubated with PDGF 100 ng/mL and IL-4 500 U/mL were significantly greater than those incubated with PDGF 100 ng/mL alone. Coincubation of PDGF with IL-4 did not significantly increase SMC u-PA antigen levels in cellular lysates. Coincubation with PDGF 100 ng/mL and IL-4 500 U/mL did not significantly affect SMC PAI-1 antigen levels in conditioned media or cellular lysates. Therefore, interleukin-4 modulates vascular SMC u-PA production induced by PDGF.     

Transforming Growth Factor β1 and Coronary Intimal Hyperplasia in Pediatric Patients With Congenital Heart Disease

Background

Congenital heart defects or the process of their repair leads to an increased risk for adult cardiovascular disease compared with the general population. Intimal hyperplasia is a preatherosclerotic lesion that may be produced as a consequence of transforming growth factor β1 (TGF-β1) pathway activation. We studied the presence of intimal hyperplasia in arteries from a pediatric population with congenital heart disease (CHD) and TGF-β1 expression to enlighten its possible role in the genesis of these lesions.

Methods

Coronary arteries from 10 controls and 98 CHD patients (54% cyanotic type, 32% surgically repaired) were stained, and the presence and degree of intimal thickening were analyzed. The expression of TGF-β1 was studied by immunohistochemistry.

Results

The difference between the presence of coronary intimal hyperplasia in patients with cyanotic (35; 66.1%) and noncyanotic CHD (29; 64.3%) was not significant. However, surgically repaired CHD presented a higher rate of coronary intimal hyperplasia (80%) than did the group without surgical intervention (47.3%), P = 0.0002. The immunostaining for TGF-β1 analyzed in samples of patients with cyanotic and noncyanotic CHD showed no significant differences. However, TGF-β1 expression was more intense on the intimal layer of patients with surgically repaired CHD than on that of those without surgery (intimal area positive for TGF-β1, 50.43% vs 15.91%, respectively; Mann-Whitney U test P = 0.0005).

Conclusion

The high incidence of intimal hyperplasia in patients with surgically repaired CHD is correlated with TGF-β1 expression and may contribute to the development of atherosclerotic coronary artery disease in CHD patients.     

Doxazosin Treatment Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Hamsters through a Decrease in Transforming Growth Factor β Secretion

Background/Aims

The development of therapeutic strategies for the treatment of cirrhosis has become an important focus for basic and clinical researchers. Adrenergic receptor antagonists have been evaluated as antifibrotic drugs in rodent models of carbon tetrachloride (CCl4)-induced cirrhosis. The aim of the present study was to evaluate the effects of carvedilol and doxazosin on fibrosis/cirrhosis in a hamster animal model.

Methods

Cirrhotic-induced hamsters were treated by daily administration of carvedilol and doxazosin for 6 weeks. Hepatic function and histological evaluation were conducted by measuring biochemical markers, including total bilirubin, aspartate aminotransferase, alanine aminotransferase and albumin, and liver tissue slices. Additionally, transforming growth factor β (TGF-β) immunohistochemistry was analyzed.

Results

Biochemical markers revealed that hepatic function was restored after treatment with doxazosin and carvedilol. Histological evaluation showed a decrease in collagen type I deposits and TGF-β-secreting cells.

Conclusions

Taken together, these results suggest that the decrease in collagen type I following treatment with doxazosin or carvedilol is achieved by decreasing the profibrotic activities of TGF-β via the blockage of α1- and β-adrenergic receptor. Consequently, a diminution of fibrotic tissue in the CCl4-induced model of cirrhosis is achieved.     

One Missense Mutation in the Factor X Gene Causing Factor X Deficiency—Factor X Kanazawa

We investigated the molecular basis of factor X deficiency in a Japanese patient whose factor X activity and antigen level were 45% and 50% of normal control values, respectively. All exons and intron/exon junctions of the factor X gene were studied using a strategy combining polymerase chain reaction (PCR) amplification and nonradioactive single-strand conformational polymorphism (SSCP) analysis. Exon 5, containing the DNA fragment of the proband, showed aberrant migration by SSCP analysis. All exon-containing DNA fragments amplified by PCR were sequenced, and it was revealed that the proband was a heterozygote for a G --> A substitution in exon 5 of the factor X gene of the proband. This mutation predicts an amino acid replacement of arginine (Arg) for glycine (Gly) at codon 114 in the second EGF-like domain.     

Suppression of the Epidermal Growth Factor Receptor Inhibits Epithelial–Mesenchymal Transition in Human Pancreatic Cancer PANC-1 Cells

Background  

Aberrant expression of epidermal growth factor receptor (EGFR) has been detected in pancreatic cancer; however, the mechanisms of EGFR in inducing pancreatic cancer development have not been adequately elucidated. The objective of this study was to determine the role of EGFR in mediating epithelial–mesenchymal transition (EMT) in pancreatic cancer cells.     

Maternal Serum Levels of Transforming Growth Factor ß1 (TGF-ß1) in Normal and Preeclamptic Pregnancies

Background: Successful pregnancy in allopregnant women depends upon the control of graft rejection mechanisms. It has been suggested that some immunosuppressive cytokines contribute to successful pregnancy and transplantation. Transforming growth factor beta (TGF-   β) exhibits potent immunoregulatory and anti-inflammatory properties which might prolong graft survival. Recent studies suggest a role for TGF- β   in the generation of T-regulatory lymphocytes which preserves the tolerance to peripheral self antigens and may control the response to allogenic tissues and thereby promote the transplantation tolerance. Also, the function of TGF-   β in trophoblast differentiation and hypertension is reported.   Objective: To evaluate the maternal serum TGF-   β1 level in normal allopregnant women and in pregnancies complicated by preeclampcia (PE).   Methods: Sixty one pregnant preeclamptic women (32 cases with severe and 29 with mild PE), 22 normotensive healthy pregnant, and 20 non-pregnant controls constituted the studied groups. The active form of TGF-   β1 in serum from all cases was investigated by indirect ELISA technique.   Results: The results showed that TGF-   β1 level was higher in all three pregnant groups as compared with the nonpregnant controls. No significant changes in serum levels of TGF-   β1 were found in PE as compared with the normal pregnancy.   Conclusion: TGF-β1 may function as a regulatory factor in fetal allograft survival during pregnancy, and TGF-   β1 does not have a pathophysiological role in PE.     

Cyclic Platelet and Leukocyte Count Oscillation in Chronic Myelocytic Leukemia Regulated by the Negative Feedback of Transforming Growth Factor β

We report a case of chronic myelocytic leukemia (CML) with cyclic oscillation of platelet and leukocyte counts and attempt to elucidate the oscillatory mechanism from the standpoint of cytokine regulation of hematopoiesis. A 57-year-old woman with a diagnosis of CML exhibited platelet and white blood cell (WBC) count fluctuations of a cyclic nature. The average duration of the cycles was about 8 weeks. The patient suffered from headache, fatigue, and malaise at the peak of the cycle. The peak thrombopoietin concentration in peripheral blood coincided with a period of decrease in platelet numbers. The change in transforming growth factor beta (TGF-beta) level paralleled that of the platelet numbers. A progenitor cell assay revealed the suppression of trilineage colony formation in the presence of plasma from the blood cell peak point, and this suppression was completely blocked when the plasma was incubated with an anti-TGF-beta antibody. From these findings, we concluded that the cyclic oscillation of the platelet, WBC, and reticulocyte counts had been induced by excess negative feedback to megakaryopoiesis by TGF-beta.     

Evidence for modulation of pericryptal sheath myofibroblasts in rat descending colon by Transforming Growth Factor β and Angiotensin II.

Background  

Absorption of water and Na⁺ in descending colonic crypts is dependent on the barrier function of the surrounding myofibroblastic pericryptal sheath. Here the effects of high and low Na⁺ diets and exposure to whole body ionising radiation on the growth and activation of the descending colonic pericryptal myofibroblasts are evaluated. In addition the effect of a post-irradiation treatment with the angiotensin converting enzyme inhibitor Captopril was investigated.     

Enhanced Expression of Transforming Growth Factor (TGF) -α Precursor and TGF-β1 During Paneth Cell Regeneration

An intravenous injection of diphenylthiocarbazone (dithizone), a zinc chelator, induces selective killing and rapid regeneration of Paneth cells, which have a large amount of zinc in their cytoplasmic granules. We examined the expression pattern of transforming growth factor (TGF) - and TGF-₁ in this regenerative process. Messenger RNA expression of TGF- and TGF-₁ reached their peaks at 12 and 24 hr after dithizone injection, respectively. Protein expression of TGF- precursor and TGF-₁ increased to a maximum at 24 and 72 hr, respectively. Their immunoreactivities were localized in the epithelial cells in the vicinity of Paneth cells, whereas they were prominent in the upper half of the crypts in control rats. In conclusion, destruction of Paneth cells induced TGF- precursor expression, followed by an increase of TGF-₁ especially in the crypt bases. This unique expression pattern of two growth factors may be involved in rapid regeneration of Paneth cells.