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Biomedical subjects

Akira Ohtsuru

Publications and source records attributed to Akira Ohtsuru.

At least 19 recordsLinked to original sources
PubMed2007

Fibrotic response to angiotensin II is blunted in the kidney, but not in the heart, in insulin-sensitive long-lived transgenic dwarf rats.

Insulin resistance is a characteristic feature of cardiovascular and renal diseases, and angiotensin II (Ang II) has been suggested to induce insulin resistance. The aims of this study were to elucidate the effect of chronic Ang II infusion on vascular reactivity and organ damage in insulin-sensitive rats. We confirmed the following three points. First, there was no significant difference in pressor response to chronic Ang II infusion (600 ng/kg/min) between insulin-sensitive transgenic rats (Tg) and control rats (C). Second, there was no significant difference in cardiac hypertrophy and fibrosis by chronic Ang II infusion between the two groups. However, third, fibrotic response to chronic Ang II infusion evaluated by histopathological scoring in the kidney was significantly decreased in insulin-sensitive transgenic rats (renal fibrosis and nephropathy score: C+Ang II vs Tg+Ang II; 2.5 vs 1.3; p<0.05). Furthermore, the expression of TGF-beta, a fibrosis indicator, was also significantly suppressed in the kidneys of the transgenic rats (TGF-beta1/GAPDH ratio: C+Ang II vs Tg+Ang II; 1.15 vs 0.81; p<0.05). This result indicates that the growth hormone/insulin-like growth factor-1 axis is critically involved in the development of renal injury and fibrosis, rather than hypertension, cardiac hypertrophy, and cardiac fibrosis induced by chronic Ang II administration.

Angiotensin II↗
PubMed2006

BRAFV600E promotes invasiveness of thyroid cancer cells through nuclear factor kappaB activation.

The BRAFV600E mutation is closely linked to tumorigenesis and malignant phenotype of papillary thyroid cancer. Signaling pathways activated by BRAFV600E are still unclear except a common activation pathway, MAPK cascade. To investigate the possible target of BRAFV600E, we developed two different cell culture models: 1) doxycycline-inducible BRAFV600E-expressing clonal line derived from human thyroid cancer WRO cells originally harboring wild-type BRAF; 2) WRO, KTC-3, and NPA cells infected with an adenovirus vector carrying BRAFV600E. BRAFV600E expression induced ERK phosphorylation and cyclin D1 expression in these cells. The BRAFV600E-overexpressing cells also showed an increase of nuclear factor kappaB (NF-kappaB) DNA-binding activity, resulting in up-regulation of antiapoptotic c-IAP-1, c-IAP-2, and X-linked inhibitor of apoptosis. Furthermore, BRAFV600E expression also induced the expression of matrix metalloproteinase and cell invasion into matrigel through NF-kappaB pathway. Increased invasive ability by BRAFV600E expression was significantly inhibited by a specific NF-kappaB inhibitor, racemic dehydroxymethylepoxyquinomicin. These data indicate that BRAFV600E activates not only MAPK but also NF-kappaB signaling pathway in human thyroid cancer cells, leading to an acquisition of apoptotic resistance and promotion of invasion. Inactivation of NF-kappaB may provide a new therapeutic modality for thyroid cancers with BRAFV600E.

Carcinoma, Papillary↗
PubMed2006

No evidence of ARAF, CRAF and MET mutations in BRAFT1799A negative human papillary thyroid carcinoma.

The MAPK signaling pathway plays a crucial role in tumorgenesis and cell proliferation in human papillary thyroid carcinoma (PTC). Ret/PTC rearrangements, RAS and BRAF mutations, the main non-overlapping genetic alterations all leading to MAPK cascade activation, are cumulatively identified in 60-80% of PTCs. In approximately one-fourth of the cases, oncogenic background potentially contributing to MAPK activation in PTC might be different. We therefore attempted to evaluate the mutational status of genes encoding other members of RAF family known to act upstream of MAPKs, ARAF and CRAF (RAF-1). In addition we also analyzed the MET gene that encodes hepatocyte growth factor/scatter factor receptor overexpressed in most of PTCs and a MAPK cascade contributor. In 129 Japanese patients with PTC, BRAF(T1799A) was detected in 65 cases (50.4%), and the remaining 64 tumor specimens were subjected to mutation analysis of kinase domains of ARAF, CRAF and MET genes, and hotspots of K- and N-RAS genes. No ARAF, CRAF, MET, K- and N-RAS mutations were revealed. Based on these observations, we concluded that despite the fact that ARAF, CRAF and MET are actively expressed, alterations of these genes are rare in PTC and unlikely to play a perceptible role in the molecular pathogenesis of this type of human malignancy.

Carcinoma, Papillary↗
PubMed2006

Pediatric CT scan usage in Japan: results of a hospital survey.

PURPOSE: The aim of this study was to examine the usage parameters of diagnostic computed tomography (CT) in children because of concerns of possible overuse in Japanese hospitals, including the "technical" CT exposure settings and the "clinical" grounds for CT requests. MATERIALS AND METHODS: We examined the methodology at the radiology department to reduce radiation exposure to children and performed a retrospective study on pediatric CT requests during a 1-year period at Nagasaki University Hospital. The parameters of diagnostic CT usage for minor head trauma and acute appendicitis were studied in detail. RESULTS: CT radiation dose settings are adjusted for children based on guidelines issued by the Japan Radiological Society, with few limitations. CT requests were made for 62% of minor head trauma cases and 76% of cases clinically suspected to be acute appendicitis. These figures are considerably higher than those reported by studies in the United Kingdom, Canada, or the United States. No specific guidelines are advocated regarding CT usage for minor head trauma. The diagnosis of acute appendicitis in children is almost routinely referred for "confirmation" by CT. CONCLUSION: CT radiation risks to children at Japanese hospitals need to be considered more seriously. Physicians should be encouraged to follow diagnostic algorithms that help avoid unnecessary CT usage in children.

Adolescent↗
PubMed2006

Selective pharmacologic inhibition of c-Jun NH2-terminal kinase radiosensitizes thyroid anaplastic cancer cell lines via induction of terminal growth arrest.

CONTEXT: The high radioresistance of anaplastic thyroid cancer (ATC) and cultured ATC cells stipulates for the means of increasing their radiosensitivity. It has been shown that c-Jun NH(2)-terminal kinase (JNK) activation is one of the manifestations of radiation response in ATC cells. OBJECTIVE: Assessment of the effect of selective JNK inhibition on ATC cell radiosensitivity and clarification of the associated mechanisms. RESULTS: The JNK inhibitor markedly suppressed ATC cell growth in a reversible cytostatic manner. The combination treatment with JNK inhibitor plus ionizing radiation induced a significant decrease in clonogenic survival of irradiated cells as compared with either singular treatment. The effect was not due to apoptosis of exposed cells but to a profound senescence-like terminal growth arrest occurring irrespectively of cells' p53 mutational status. Postradiational DNA damage repair was also significantly compromised in the presence of SP600125. CONCLUSIONS: JNK signaling is an essential component of ATC cell proliferation and survival after radiation therapy. Hence, pharmacological interference with JNK pathway in combination with radiotherapy may be a promising treatment of ATC.

Activating Transcription Factor 2↗
PubMed2006

Heat-directed suicide gene therapy mediated by heat shock protein promoter for gastric cancer.

The prognosis of patients with metastatic gastric cancer, particularly peritoneal carcinomatosis, remains poor despite intensive interventions. Gene therapy and hyperthermia can be promising strategies for such advanced disease. The study was conducted to explore the possible effective therapeutic approach of suicide gene therapy with herpes simplex virus thymidine kinase (HSV-tk) in combination with hyperthermia for advanced gastric cancer. The heat shock protein (hsp) 70B gene promoter-oriented HSV-tk (HSP-tk)/ganciclovir (GCV) system directed by heat shock was developed. Hsp promoter activity under the control of heating was assessed by dual luciferase assay in gastric cancer cell lines and implanted tumors of nude mice. In vitro cytotoxic assay was performed using the HSP-tk/GCV delivered by the hemagglutinating virus of Japan (HVJ) liposome, with or without heating. Mice with subcutaneously xenografted tumors and peritoneal carcinomatosis were treated with hyperthermia and gene therapy using the HVJ-liposome-carrying HSP-tk. Assessment by luciferase assay demonstrated highly inducible and tumor-specific promoter activity in vitro and in vivo. Cytotoxic assays showed that cells transfected with HSP-tk became more sensitive to GCV with heating. A synergistic effect was also observed when treated with a non-heat-inducible cytomegalovirus (CMV) promoter-mediated HSV-tk/GCV and heating, indicating bystander killing. The HVJ-liposome-carrying HSP-tk/GCV combined with hyperthermia significantly inhibited the growth of subcutaneous tumors and prolonged survival of mice with peritoneal carcinomatosis. We conclude that the combination of suicide gene therapy with hyperthermia can provide a promising treatment modality for advanced gastric cancer.

Animals↗
PubMed2006

Childhood thyroid carcinoma with BRAFT1799A mutation shows unique pathological features of poor differentiation.

The prevalence of BRAFT1799A mutation in papillary thyroid carcinomas (PTCs) displays a marked age association: relatively high in adults and exceedingly low in childhood. We report a case of a 12-year-old Japanese female with PTC, the only one case that harbored BRAFT1799A mutation in a series of 46 childhood thyroid cancer tissues. On histology, the findings were so atypical that pathologists had repeatedly examined tumor sections to agree on the diagnosis of poorly differentiated follicular carcinoma. Upon molecular investigation, BRAFT1799A was detected in DNA extracted from paraffin-embedded material, whereas TP53 was wild-type. Since BRAFT1799A is strictly limited to PTCs, immunohistochemical staining for CD15, a specific marker for papillary carcinoma, was performed to verify the diagnosis. A small tumor area with papillary-like structure was stained positive. These findings strongly suggest that this case is a poorly differentiated carcinoma that arose from PTC and implies a possible association of BRAF mutation with dedifferentiated phenotype of PTCs.

Carcinoma, Papillary↗
PubMed2005

The efficacy and safety of gene transfer into the porcine liver in vivo by HVJ (Sendai virus) liposome.

BACKGROUND: Gene transfer systems using viral vectors are efficient; however, most viral vectors also tend to evoke immunologic reactions, thereby clinically causing serial side effects. HVJ-liposome vector is a hybrid vector consisting of liposome and an inactivated Sendai virus (Hemmagglutinating Virus of Japan [HVJ]), which has been reported to be less immunogenic and can also be repeatedly administered. We examined the usefulness of this vector for hepatic gene therapy in a pig model. METHODS: Genes encoding beta-galactosidase and luciferase were used as reporter genes. The pigs were injected with the reporter gene loaded-HVJ-liposome into the portal vein under total vascular exclusion of the liver. The transfection efficiencies were then assessed by beta-galactosidase staining, a luciferase assay, and RT-PCR for LacZ mRNA. Biochemical and histologic analyses were performed to evaluate tissue toxicity after gene transfer. RESULTS: The luciferase gene expression in the liver reached its highest level at 7 days after transfection. It continued to be detected up to 28 days after transfection, while all pigs remained healthy throughout the observation period. The transfection efficiency was 15% in the hepatocytes according to beta-galactosidase staining. Extrahepatic transgene expression was slightly observed in the lung and kidney, but not in the spleen or ovary. CONCLUSIONS: These data suggest for the first time that the use of the HVJ-liposome vector is a safe and feasible modality for liver-directed gene transfer in pigs, and it might therefore be suitable for clinical gene therapy trials.

Animals↗
PubMed2005

Total vascular exclusion safely facilitates liver specific gene transfer by the HVJ (sendai virus)-liposome method in rats.

BACKGROUND: Most virus mediated transfection systems are efficient; however, their highly immunogenic properties do tend to cause clinical problems. HVJ-liposome vector is a hybrid vector consisting of liposome and inactivated sendai virus (hemagglutinating virus of Japan HVJ), which has been reported to be have a low immunogenicity, while it can also be repeatedly administered. To enhance the transfection efficiency, especially in the liver, we investigated the efficacy of total vascular exclusion (TVE) during the portal vein injection (PVI) of the vectors. MATERIALS AND METHODS: beta-galactosidase and luciferase expression were used as reporter genes. Wistar rats were injected with HVJ-liposome through PVI without TVE (PVI group, n = 10) or PVI with TVE (PVI + TVE group, n = 10). The control rats were infused with equal volumes of saline through the portal vein (control group n = 12). The transfection efficiencies were assessed by beta-galactosidase staining and a luciferase assay. Biochemical and histological analyses were performed to evaluate the tissue toxicity after gene transfer. RESULTS: The reporter genes expression in the liver dramatically increased after PVI + TVE in comparison to after PVI alone (1.2 x 10(5)versus 1.5 x 10(4) RLU/mg protein, P < 0.05 according to a luciferase assay). Notably, the extrahepatic "leaky" transgene expression could be minimized by PVI + TVE, whereas the general condition remained unchanged according to both the biochemical parameters and histological findings. CONCLUSIONS: The present data indicate that PVI + TVE may thus facilitate the liver-specific gene delivery using the HVJ-liposome method and this modality might also be applicable to other gene transfer systems.

Animals↗
PubMed2005

A novel molecular marker of pituitary tumor transforming gene involves in a rat liver regeneration.

BACKGROUND: Pituitary tumor transforming gene (PTTG), homologous to a mammalian securin, plays a pivotal role in cell transformation, however, its biological function(s) in normal tissues is not fully understood. Because the liver is a regenerative organ, the relevant biological function of PTTG in the liver would be more feasible to understand PTTG. Also, PTTG may be involved in the liver regeneration. MATERIALS AND METHODS: Expressions of rat hepatic PTTG messengerRNA (mRNA) and cellular immunoreactivities during the cell proliferative period of the liver regeneration both in vitro and in vivo were tested. RESULTS: PTTG expression of the rat primary hepatocyte was stimulated by HGF in a dose dependent manner, and was suppressed when hepatocyte proliferation was inhibited by transforming growth factor-beta1. A positive PTTG immunoreactive co-localizing with 5-bromo-2'-deoxyuridine (BrdU) in the hepatocyte nucleus was found and there was a concurrent sister chromatin itself by the immunofluorescent labeling of PTTG with cytokeratin 18 (CK18). DISCUSSION: Since the correlation of PTTG mRNA expression, cell proliferation and immunoreactivity were observed in primary rat cultured hepatocytes, PTTG may be a novel marker of cell proliferation both in vitro and in vivo liver regeneration.

Animals↗
PubMed2005

Radiation-induced senescence-like terminal growth arrest in thyroid cells.

Premature senescence may play an important role as an acute, drug-, or ionizing radiation (IR)-inducible growth arrest program along with interphase apoptosis and mitotic catastrophe. The aim of the study was to evaluate whether IR can induce senescence-like phenotype (SLP) associated with terminal growth arrest in the thyroid cells, and if so, to evaluate impact of terminal growth arrest associated with SLP in intrinsic radiosensitivity of various thyroid carcinomas. The induction of SLP in thyroid cells were identified by: (1) senescence associated beta-galactosidase (SA-beta-Gal) staining method, (2) dual-flow cytometric analysis of cell proliferation and side light scatter using vital staining with PKH-2 fluorescent dye, (3) double labeling for 5-bromodeoxyuridine and SA- beta-Gal, (4) Staining for SA-beta-Gal with consequent antithyroglobulin immunohistochemistry. IR induced SLP associated with terminal growth arrest in four thyroid cancer cells lines and in primary thyrocytes in time- and dose-dependent manner. Analysis of relationship between induction of SLP and radiosensitivity revealed a trend in which more radioresistant cell lines strongly tended to show lower specific SLP yields (r = -0.93, p = 0.068). We find out that SA-beta-Gal staining is detectable in irradiated ARO xenotransplants, but not in control tumors. We, therefore, conclude that induction of SLP with terminal growth arrest contribute to the elimination of clonogenic populations after IR.

Animals↗
PubMed2005

Impact of Helicobacter pylori infection on gastric and plasma ghrelin dynamics in humans.

OBJECTIVES: There are contradictory reports on the relationship between Helicobacter pylori and circulating ghrelin. We sought to clarify the influence of H. pylori infection on gastric and plasma ghrelin dynamics in humans. METHODS: Using endoscopic biopsies from the corpus of 56 H. pylori-infected patients and 25 uninfected subjects, ghrelin mRNA expression levels and gastric ghrelin peptide contents were measured by real-time polymerase chain reaction and radioimmunoassay, respectively. We also measured plasma ghrelin concentrations and analyzed the numbers of ghrelin immunoreactive cells in the fundic gland area. Fifty-one patients with H. pylori infection were treated with a 7-day triple therapy consisting of lansoprazole, clarithromycin, and amoxicillin. RESULTS: The gastric ghrelin mRNA expression level of H. pylori-positive patients (1.64 +/- 1.27 in arbitrary units) was significantly lower than in H. pylori-negative subjects (4.87 +/- 4.1, p < 0.0001). A similar trend was noted for ghrelin peptide contents (31.2 +/- 27.5 vs 81.2 +/- 64.1 ng/mg protein, respectively, p < 0.0001). There was no significant difference in the number of ghrelin immunoreactive cells/mm(2) in terms of H. plyori status. Plasma ghrelin concentrations in H. pylori-infected patients (144.6 +/- 7.8.8 fmol/ml) were significantly lower than in uninfected subjects (196.1 +/- 97.2, p < 0.05) and increased following cure of the infection. Plasma ghrelin levels correlated positively with the expression levels of ghrelin mRNA (r = 0.583, p < 0.0001) and peptide products (r = 0.574, p < 0.0001). There was a significant stepwise decrease in gastric ghrelin mRNA expression (p < 0.05), peptide contents (p < 0.01) and density of ghrelin immunoreactive cells (p < 0.05) with progression of histological severity of glandular atrophy in the corpus. The histological severity of chronic inflammation also negatively influenced the ghrelin mRNA expression (p < 0.001) and peptide production (p < 0.005). CONCLUSIONS: H. pylori infection has a negative impact on gastric and plasma ghrelin dynamics. Chronic inflammatory and atrophic changes associated with the infection may affect gastric ghrelin biosynthesis and contribute to the low circulating levels.

Adult↗
PubMed2005

Plasma concentrations of adrenomedullin and ghrelin in hemodialysis patients with sustained and episodic hypotension.

Sustained and/or episodic hypotension during hemodialysis (HD) is an important clinical issue. Plasma adrenomedullin (AM) is increased in HD patients with sustained hypotension, but little is known about its implications for episodic hypotension. Ghrelin may also contribute to the pathophysiology of hypotension in HD patients. We evaluated plasma levels of AM and total ghrelin in sustained hypotensive (SH; n = 23), episodic hypotensive (EH; n = 30) and normotensive (NT; n = 23) HD patients. In the EH group, the relationship between low blood pressure during HD and circulating levels of AM and ghrelin was also evaluated. Plasma levels of AM were significantly higher in SH (34.3 +/- 8.3 fmol/ml, p<0.01) than in NT patients (27.6 +/- 5.2 fmol/ml), but not in EH patients (30.8 +/- 6.1 fmol/ml). There was no significant difference of plasma total ghrelin in SH (548.1 +/- 426.5 fmol/ml) and in EH patients (544.6 +/- 174.3 fmol/ml), compared with NT patients (400.0 +/- 219.7 fmol/ml). On the other hand, in EH patients, the "suppressed blood pressure ratio" during HD significantly correlated with plasma AM (r = 0.77, p<0.001) and with total ghrelin levels (r = 0.44, p<0.05). Our results suggest that ghrelin, as well as AM, may play an important role as vasodilator local hormones and regulation of blood pressure during HD, especially the occurrence of EH. Further studies are necessary to clarify the implication of these hormones in the control of hypotension during HD.

Adrenomedullin↗
PubMed2005

Vitamin D3 treatment for locally advanced thyroid cancer: a case report.

There are many intricacies in the surgical treatment of locally advanced thyroid cancer, including the medical management of the remaining functional organ and any cosmetic impairments, which are sometimes very difficult to manage and eventually carry a relatively high morbidity and mortality. Here, we report on a case of a 65-year-old female with an extremely locally-advanced thyroid cancer involving both lobes of the thyroid, blood vessels, trachea and esophagus. Despite the severity of her condition, oral administration of vitamin D3 (alphacalcido) has stalled both the tumor growth and further increases of serum thyroglobulin (Tg) level, and has led to a good preservation of quality of life for the last two years. Several reports have previously demonstrated the efficacy of vitamin D3 to inhibit the proliferation of thyroid cancer cell lines in vitro, but clinical evidence has been limited so far. Therefore, this case report provides important evidence for the effectiveness of vitamin D3 therapy against advanced thyroid cancers.

Aged↗
PubMed2005

Clinical significance of categorisation of mammographic density for breast cancer prognosis.

Mammographic density reflects comprehensive changes in the mammary gland. The condition of the tumour microenvironment is a possible factor affecting tumour progression, as well as a tumour risk factor. This study aimed to determine whether mammographic density correlates with tumour clinicopathological features and prognosis in breast cancer patients. The analysis involved 163 Japanese women who underwent surgery for breast cancer between 1999 and 2003 in the Nagasaki University Hospital, Japan. Mammographic density was classified according to the breast imaging reporting and data system (BI-RADS) categories 1-4. Age, tumour size, axillary lymph node involvement, steroid receptor (SR) status, histological grade and Nottingham prognostic index (NPI) were analysed by density category and tested for statistically significant differences across categories. A significant difference (P<0.05) by breast-density category was found only for age. SR-negative tumours had significantly worse NPI scores than SR-positive tumours in breast-density categories 2 (P=0.03) and 4 (P<0.001). A high distant-metastasis frequency was observed in category 4 SR negatives (44%) versus category 4 SR positives (4.3%). These findings reveal that although the BI-RADS breast-density category alone is not associated with prognosis in breast cancer, patients who are both category 4 and SR negative have an extremely poor prognosis.

Age Factors↗
PubMed2004

Induction of thyroid cancer cell apoptosis by a novel nuclear factor kappaB inhibitor, dehydroxymethylepoxyquinomicin.

PURPOSE: The objective of the study was to determine the effects of a novel selective nuclear factor kappaB (NF-kappaB) inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in thyroid carcinoma cells in vitro and in vivo and to additionally elucidate the molecular mechanisms underlying the action of this chemotherapeutic agent. EXPERIMENTAL DESIGN: In the in vitro experiments, the induction of apoptosis by DHMEQ in various human thyroid carcinoma cell types was determined by flow cytometry analysis of annexin-V binding and the caspase activation by Western blotting. For the in vivo study, female nu/nu mice were xenografted with s.c. FRO thyroid tumors. DHMEQ solution was injected i.p. at a dose of 8 mg/kg/day for two weeks. Tumor dimensions were monitored twice weekly, and apoptosis in tumor specimens was determined by terminal deoxynucleotidyl transferase-mediated nick end labeling staining. RESULTS: Treatment with DHMEQ substantially inhibited the translocation of p65 and p50 NF-kappaB subunits to the nucleus, the DNA-binding activity of the RelA/p65, NF-kappaB-dependent expression of the inhibitor of apoptosis (IAP)-family proteins, cIAP-1, cIAP-2, and XIAP, and the de novo synthesis of inhibitor of nuclear factor kappaB alpha. At concentration levels ranging from 0.1 to 5 microg/ml, DHMEQ induced a caspase-mediated apoptotic response that could be abrogated by the c-Jun NH(2)-terminal kinase inhibitor SP600125 but not by either mitogen-activated protein/extracellular signal-regulated kinase kinase or p38 inhibitors. In contrast, normal human thyrocytes were resistant to DHMEQ-induced apoptosis. At higher doses of DHMEQ we observed the necrotic-like killing of both normal and malignant thyrocytes, which was resistant to mitogen-activated protein kinase inhibitors. In nude mice DHMEQ substantially inhibited tumor growth without observable side effects, and increased numbers of apoptotic cells were observed in the histologic sections of tumors treated with DHMEQ. CONCLUSIONS: Our results show the potential usefulness of the novel NF-kappaB inhibitor, DHMEQ, in future therapeutic strategies for the treatment of thyroid cancers that do not respond to conventional approaches.

Apoptosis↗
PubMed2004

GH suppresses TGF-beta-mediated fibrosis and retains cardiac diastolic function.

The aims of this study were to elucidate the molecular mechanism by which growth hormone (GH) excess is anti-fibrotic in vitro and in vivo model. The in vivo model GH excess showed a significant increase of relative wall thickness with no concomitant disturbance of cardiac diastolic function. Western blot for extracellular matrix (ECM) structural proteins showed minimal change in the GH treatment group, compared to an Angiotensin II (Ang II) subpressor dose group. In cultured cardiac fibroblasts, we investigated the abundance of ECM proteins, phosphorylation of p38 mitogen-activated protein kinase (MAPK), and transforming growth factor-beta (TGF-beta)-specific transcriptional activity. GH down-regulated the expression of PAI-1 and fibronectin proteins activated by TGF-beta. In reporter assays, GH, but not insulin-like growth factor-1 (IGF-1), reduced TGF-beta-specific transcriptional activity. Moreover, GH markedly down-regulated TGF-beta-induced phosphorylation of p38 MAPK. These results demonstrated that a chronic excess of GH have an anti-fibrotic effect on cardiac remodeling, probably through a down-regulation of TGF-beta signaling via de-phosphorylation of p38 MAPK.

Angiotensin II↗