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Biomedical subjects

Daisuke Goto

Publications and source records attributed to Daisuke Goto.

At least 37 records · Page 2Linked to original sources
PubMed2005

Analysis of abnormally expressed genes in synovium from patients with rheumatoid arthritis using a column gel electrophoresis-coupled subtractive hybridization technique.

Rheumatoid arthritis (RA) is a chronic disease of unknown pathogenesis. To identify abnormally expressed genes in synovium from RA patients, we performed column gel electrophoresis-coupled subtractive hybridization (CGESH). CGESH is a newly developed subtractive hybridization technique to achieve sufficient enrichment of DNA sequences. CGESH was performed using restricted enzyme digested cDNA synthesized from mRNA of synovial tissues from one RA patient and one osteoarthritis (OA) patient. The obtained subtraction libraries (RA-OA) were screened by dot blot hybridization. The clones showing higher hybridization with the RA-OA probe were identified by sequence analysis and homology search. Their DNA sequencing revealed that the genes of HLA-DRB1, sequestosome 1, elongation factor 1alpha were included. Furthermore, a functionally unknown gene (FLJ00133) was also identified. It is reported that sequestosome 1 is a scaffold in the signal transduction of TNFalpha and interleukin 1, which are the important cytokines involved in the pathogenesis of RA. It is possible that other genes identified by the CGESH technique would be associated with the pathogenesis of RA, although there is no direct evidence yet. Our results imply that the CGESH technique is a useful tool to detect genes involved in the pathogenesis of RA. Further investigation of the functional roles of candidate genes should shed light on the pathogenesis of RA.

Arthritis, Rheumatoid↗
PubMed2005

The exploration of joint-specific immunoreactions on immunoglobulins G of anti-glucose-6-phosphate isomerase antibody-positive patients with rheumatoid arthritis.

The pathogenic role of autoantibodies in rheumatoid arthritis (RA) remains elusive. Anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) are candidates for arthritogenic Abs because they directly induce arthritis in mice. High titers of anti-GPI Abs are found in some RA patients with severe forms. The aim of this study was to analyze the role of IgG, including anti-GPI Abs, in the joints of RA patients. Synovial tissue was obtained from 6 patients with RA (3 anti-GPI Abs- positive and 3 anti-GPI Abs- negative) and compared histologically and immunohistochemically for IgG and C3 deposition. IgG fractions were separated from the sera of anti-GPI Abs-positive RA patients and healthy subjects, and injected into the metacarpophalangeal joints of 4 cynomolgus monkeys. On day 16, the joints were harvested and examined histologically and immunohistochemically. The expression of the C5a receptor (C5aR) molecule in the synovium was quantified by real-time PCR using cDNA from the monkeys' joints. The synovia of anti-GPI Abs-positive RA patients showed diffuse infiltration of cells, including mast cells, and strong deposition of IgG and C3. In monkeys, IgG from RA patients, including anti-GPI Abs, resulted in recruitment of granulocytes and mononuclear cells, strong deposition of IgG on the articular surface, and overexpression of C5aR, but no joint swelling. No infiltrated cells or IgG deposition were observed in monkeys injected with IgGs from healthy subjects. Our results suggest that IgG fraction from RA patients, including that of anti-GPI Abs, may play a role in the synovitis of RA, although the pathogenesis of human anti-GPI Abs is still uncertain.

Animals↗
PubMed2004

Glucose-6-phosphate isomerase variants play a key role in the generation of anti-GPI antibodies: possible mechanism of autoantibody production.

Glucose-6-phosphate isomerase (GPI), recognized as an autoantigen in the K/BxN arthritis model, is a ubiquitous cytoplasmic enzyme. Anti-GPI antibodies (Abs) are also detected in the serum of patients with arthritic diseases including rheumatoid arthritis (RA). So far, 24 GPI variants have been reported and most of these variants relate to non-spherocytic hemolytic disease. To understand the mechanisms of anti-GPI Ab production, cDNAs from peripheral blood mononuclear cells of subjects with or without anti-GPI Abs were cloned and sequenced. We identified 39 new GPI variants (57-1596 bp). The frequency of GPI variants in healthy control subjects (HS) with anti-GPI Abs (27/73, 31.5%) was significantly higher than that in anti-GPI Ab-negative HS (5/78, 6.4%, p < 0.001). The frequency of GPI variants in anti-GPI Ab-positive RA patients (22/77, 28.6%) was more significantly higher than in anti-GPI Ab-negative patients (1/63, 1.6%, p < 0.0001). Our results suggest that GPI variants may play a crucial role in the production of autoantibodies against ubiquitous GPI autoantigens.

Arthritis, Rheumatoid↗
PubMed2004

Tacrolimus impairment of insulin secretion in isolated rat islets occurs at multiple distal sites in stimulus-secretion coupling.

Tacrolimus causes posttransplant diabetes mellitus, although the pathogenetic mechanisms remain controversial. We studied the mechanism of tacrolimus-induced impairment of insulin secretion using isolated rat pancreatic islets. Tacrolimus caused reductions in DNA and insulin contents per islet during 7-d culture. Tacrolimus time-dependently suppressed glucose-stimulated insulin secretion, and at a therapeutic concentration of 0.01 micromol/liter, it suppressed glucose-stimulated insulin secretion to 32 +/- 5% of the control value after 7-d incubation. Tacrolimus did not change islet glucose utilization and oxidation, ATP production, insulin mRNA expression, or the capacity for high glucose to increase intracellular Ca(2+), but altered the rapid frequency oscillations of Ca(2+) concentration. Tacrolimus suppressed insulin secretion stimulated by mitochondrial fuel (combination of l-leucine and l-glutamine, and alpha-ketoisocaproate) and glibenclamide, but not by l-arginine. Tacrolimus suppressed insulin secretion induced by carbachol and by a protein kinase C agonist in the presence or absence of extracellular Ca(2+). Under stringent Ca(2+)-free conditions, tacrolimus did not affect mastoparan-induced insulin secretion, but suppressed its glucose augmentation. Our results suggest that tacrolimus impairs glucose-stimulated insulin secretion downstream of the rise in intracellular Ca(2+) at insulin exocytosis, and that protein kinase C-mediated (Ca(2+)-dependent and independent) and Ca(2+)-independent GTP signaling pathways may be involved. However, tacrolimus-induced impaired insulin secretion was reversed 3 d after removal of the drug. Our study demonstrated that tacrolimus impairs insulin secretion at multiple steps in stimulus-secretion coupling.

Adenosine Triphosphate↗
PubMed2004

Reiter's syndrome following intravesical bacille biliE de Calmette-GuErin treatment for superficial bladder carcinoma: report of six cases.

We report the cases of six patients who developed acute Reiter's syndrome following intravesical bacille biliE de Calmette-GuErin (BCG) immunotherapy for superficial bladder cancer. After the third to eighth BCG intravesical injection, the patients developed conjunctivitis, aseptic urethritis, and polyarthritis consistent with a diagnosis of Reiter's syndrome. HLA-B27 antigen was negative in five of the patients examined. Two of the patients responded to nonsteroidal anti-inflammatory drugs for polyarthritis, and the other four responded to steroids (prednisolone 5-10 mg/day). The frequent use of intracavitary BCG may increase the incidence of BCG-induced Reiter's syndrome. Further analysis of the relationship between HLA-B and -DR alleles and arthritis should shed light on the mechanism of BCG-induced Reiter's syndrome.

Journal Article↗
PubMed2004

Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity.

Obesity and insulin resistance confer increased risk for accelerated coronary disease and cardiomyopathic phenomena. We have previously shown that inhibition of angiotensin-converting enzyme (ACE) prevents coronary perimicrovascular fibrosis in genetically obese mice that develop insulin resistance. This study was performed to elucidate mechanism(s) implicated and to determine the effects of attenuation of angiotensin II (Ang) II. Genetically obese ob/ob mice were given ACE inhibitor (temocapril) or Ang II type 1 (AT(1)) receptor blocker (olmesartan) from 10 to 20 weeks. Cardiac expressions of plasminogen activator inhibitor (PAI)-1, the major physiologic inhibitor of fibrinolysis, and transforming growth factor (TGF)-beta(1), a prototypic profibrotic molecule, were determined and extent of perivascular coronary fibrosis was measured. Twenty-week-old obese mice exhibited increased plasma levels of PAI-1 and TGF-beta(1) compared with the values in lean counterpart. Perivascular coronary fibrosis in arterioles and small arteries was evident in obese mice that also showed increased left ventricular collagen as measured by hydroxyproline assay. Immunohistochemistry confirmed the deposition of perivascular type 1 collagen. Markedly increased PAI-1 and TGF-beta were seen immunohistochemically in coronary vascular wall and confirmed by western blotting. When obese mice were treated with temocapril or olmesartan from 10 to 20 weeks, both were equally effective and prevented increases in perivascular fibrosis, plasma PAI-1 and TGF-beta(1), left ventricular collagen and mural immunoreactivity for PAI-1, TGF-beta and collagen type 1. The c-Jun NH(2)-terminal kinase (JNK) activity was elevated in the left ventricle of obese mice (western) and blocked by temocapril and olmesartan. Ang II-mediated upregulation of PAI-1 and TGF-beta(1) with collagen deposition may explain the mechanism of perivascular fibrosis in obese mice. ACE inhibition and blockade of AT(1) receptor may prevent coronary perivascular fibrosis and collagen deposition even before development of overt diabetes. JNK activation may be a mediator of obesity-related cardiac dysfunction and a potential therapeutic target.

Angiotensin II↗
PubMed2004

Polymorphisms of IL-1 beta gene in Japanese patients with Sjögren's syndrome and systemic lupus erythematosus.

OBJECTIVE: Interleukin (IL)-1 beta is a proinflammatory cytokine involved in various immune responses. Five polymorphisms in the IL-1 beta gene have been described, and relationships between these polymorphisms and some autoimmune diseases have been reported. Evidence suggests that IL-1 beta may be involved in the destruction of salivary and lacrimal glands in Sjögren's syndrome (SS). We evaluated the significance of IL-1 beta gene polymorphisms in SS. METHODS: Blood samples were taken from 101 patients with SS, 103 patients with systemic lupus erythematosus (SLE, excluding those with secondary SS), and 106 healthy volunteers. Each polymorphism of the IL-1 beta gene was analyzed by polymerase chain reaction (PCR) amplification of the polymorphic site, followed by site-specific restriction digestion. Genotype frequencies of each polymorphism in SS patients were compared with those of the controls and SLE patients, and differences between primary and secondary SS patients were also compared. RESULTS: Genotypes CC, TT, and AA in positions -511, -31, and 3877, respectively, were significantly less frequent in SS patients than controls or patients with SLE. No significant differences were found in genotype frequencies of any of the polymorphisms between patients with primary SS and secondary SS. CONCLUSION: IL-1 beta gene polymorphisms may affect susceptibility to SS, but not SLE.

DNA↗
PubMed2004

Expression of tristetraprolin (G0S24) mRNA, a regulator of tumor necrosis factor-alpha production, in synovial tissues of patients with rheumatoid arthritis.

OBJECTIVE: To determine the significance of tristetraprolin (TTP) gene expression in synovial tissues of patients with rheumatoid arthritis (RA). METHODS: Gene expression was examined in synovial tissue and peripheral blood lymphocytes of a patient with RA by differential display-polymerase chain reaction (PCR). One of the identified genes, TTP, was selected for further analysis. cDNA was prepared from synovial tissues of 22 patients with RA and 22 with osteoarthritis (OA). Expression of TTP and tumor necrosis factor-a (TNF-a) genes was measured by TaqMan real-time semiquantification PCR. In RA samples, expression of TTP mRNA was compared with TNF-a mRNA, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and steroid and/or disease modifying antirheumatic drug use. RESULTS: Expression of TTP gene was significantly higher in synovial tissues of RA patients than in OA. There was no apparent relationship between expression of TTP and TNF-a genes. TTP gene expression had a tendency to be inversely correlated with serum CRP, measured immediately before surgery. In addition, CRP was higher in patients with a low TTP/TNF-a gene expression ratio (p = 0.0071, Spearman rank correlation). CONCLUSION: A low TTP/TNF-a gene expression ratio could indicate failure of RA patients to produce adequate amounts of TTP in response to increased TNF-a production. Inappropriate TTP production may be one factor that contributes to higher RA disease activity.

Arthritis, Rheumatoid↗
PubMed2003

Induction of Tissue Factor Expression in Endothelial Cells by Basic Fibroblast Growth Factor and its Modulation by Fenofibric acid.

BACKGROUND: Tissue factor (TF), expressed in endothelial cells (ECs) and enriched in human atherosclerotic lesions, acts as a critical initiator of blood coagulation in acute coronary syndrome. Basic fibroblast growth factor (bFGF) induces the proliferation and migration of ECs and plays a role in angiogenesis and restoration of endothelial integrity. As TF is implicated in angiogenesis, we studied the effect of bFGF on TF gene and protein expression. Methods: Human umbilical vein ECs (HUVECs) were exposed to bFGF. TF mRNA was assessed by Northern blot and TF protein was assessed by Western blot. TF promoter activity was assessed by transient transfection assay and transcription factor was identified by electro mobility shift assay. RESULTS: bFGF increased TF mRNA and protein expression in HUVECs. Increased TF mRNA was attenuated by inhibition of extracellular signal-regulated kinase kinase in human ECV304 cells. Transient transfection assays of the human TF promoter-luciferase construct (-786/+121 bp) demonstrated that bFGF induced transcription was dependent on the elements within the -197 to -176 bp relative to the transcription start site of the human TF gene. This region contains NF-kappaB like binding site. Electro mobility shift assay showed that bFGF increased nuclear translocation or DNA binding of NF-kappaB transcription factor to TF promoter. Nucleotide substitution to disrupt NF-kappaB like site reduced bFGF stimulated promoter activity. Fenofibric acid, an agonist ligand for the peroxisome proliferator activated receptor-alpha, reduced basal and bFGF stimulated TF expression. CONCLUSIONS: These results indicate that bFGF may increase TF production in ECs through activation of transcription at NF-kappaB binding site, and control coagulation in vessel walls. Fibrate can inhibit TF expression and therefore reduce the thrombogenecity of human atherosclerotic lesions.

Journal Article↗
PubMed2003

Intracellular signal transduction modulating expression of plasminogen activator inhibitor-1 in adipocytes.

The concentrations in blood of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis and proteolysis, are elevated in obese and insulin-resistant subjects, predispose them to the risk of thrombosis, and may accelerate atherogenesis. Adipose tissue is a prominent source. Accordingly, intracellular signaling pathways that may influence PAI-1 expression in adipocytes have been the focus of considerable study. Rho, a small GTP binding and GTPase protein, when activated in turn activates its target, Rho-associated coiled-coil forming protein, to yield an active kinase, Rho-kinase, an effector in the Rho pathway. Rho-kinase exerts calcium-sensitizing effects in vascular smooth muscle cells and inhibitory effects on transforming growth factor-beta (TGF-beta) expression in chicken embryonic heart cells. Because TGF-beta is a powerful agonist of PAI-1 expression, we characterized the effects of inhibition of Rho-kinase in 3T3-L1 adipocytes. PAI-1 mRNA was determined by Northern blotting, and PAI-1 protein was determined by Western blotting. The Rho-kinase inhibitor, Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide], increased PAI-1 expression markedly. Although genistein, a flavonoid tyrosine kinase, attenuated the increase of PAI-1 induced by Y-27632, other non-flavonoid tyrosine kinase inhibitors did not. However, another flavonoid, daidzein, which lacks tyrosine kinase activity, decreased basal PAI-1 expression and attenuated the induction of PAI-1 expression by Y-27632. Thus, the Rho/Rho-kinase system inhibits PAI-1 expression by a flavonoid-sensitive mechanism in adipocytes. Therefore, flavonoids may be useful in decreasing elevated PAI-1 expression in adipose tissue and its consequent pathophysiologic sequelae.

3T3 Cells↗
PubMed2003

Mannose binding lectin gene polymorphism in patients with type I diabetes.

Our purpose was to investigate a possible relationship between occurrence of type I diabetes and polymorphism of the mannose binding lectin gene. Polymorphism of codon 54 of the mannose binding lectin (MBL) gene, whose presence of the minority allele leads to significant reduction of serum MBL concentration, was investigated in 128 Japanese patients with type I diabetes and 78 healthy volunteers by restriction fragment length polymorphism method. Frequencies of the minority allele were compared between the patient group and the control group. Frequency of the minority allele was 24.2% in the patient group and 19.9% in the control group. The probability of being heterozygous or homozygous for the minority allele was 41.4% in the patient group and 33.3% in the control group. Patients with DRB1*0405-DQB1*0401 and/or DRB1*0901-DQB1*0303 haplotypes, the two major type I diabetes-prone human leukocyte antigen haplotypes, showed a slightly higher probability of being heterozygous or homozygous for allele B of the MBL gene. Possession of the minority allele of the MBL gene may be a minor risk factor for having type I diabetes.

Age of Onset↗
PubMed2003

Prevalence of hepatitis viral infection in dental patients with impacted teeth or jaw deformities.

OBJECTIVE: The prevalence of infection with hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis G virus (HGV), and transfusion-transmitted viruses (TTV) was evaluated in patients with impacted teeth or jaw deformities. STUDY DESIGN: Of 486 patients, 268 had serum samples available for retrospective TTV DNA and HGV RNA assays. In addition, the sera of 404 patients were assayed for HB surface antigen and the sera of 340 were assayed for HCV antibody. RESULTS: HGV RNA was detected in 3 of 268 patients (1.1%), and TTV DNA was detected in 60 of 268 (22.4%). Of 404 patients, 3 had HB surface antigens (0.7%). Furthermore, 13 of 340 were HCV-seropositive (3.8%). The rate of infection was similar between patients with impacted teeth and those with jaw deformities, respectively, as follows: 1.1% versus 0%, respectively, for HBV prevalence; 4.1% versus 3.2% for HCV prevalence; 1.8% versus 0% for HGV prevalence; and 22.9% versus 21.4% for TTV prevalence. CONCLUSIONS: Universal precautions to prevent hepatitis and TTV infection during oral surgical procedures are important.

Adult↗
PubMed2003

Coronary capillary network remodeling and hypofibrinolysis in aged obese diabetic rats: implications for increased myocardial vulnerability to ischemia.

Despite the known abnormalities of cardiac function in patients with overt non-insulin dependent diabetes mellitus (NIDDM) the temporal changes of coronary capillary network remodeling leading to potential microcirculatory dysfunction have not been elucidated. To this end, left ventricular subendocardial capillary network of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, characterized by hypertension, obesity, hyperglycemia, hyperinsulinemia and mild NIDDM, and control Long-Evans Tokushima (LETO) rats were investigated. Total capillary density in OLETF was significantly higher than that in LETO at 20 weeks, suggesting compensatory improvement of O2 transport at early stages of NIDDM. The increase in capillary density in OLETF was lost at 40 and 60 weeks due to the decreases of intermediate capillary portions and venular capillary portions. Although capillary domain area (area innervated by single capillary) in OLETF was lower than that in LETO at 20 weeks, the values were similar between OLETF and LETO at 40 and 60 weeks, suggesting that adaptive improvement in the capacity for 02 transport with a high perfusion was lost in late stages of NIDDM. Activity of plasma plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of proteo(fibrino)lysis, in OLETF was higher than that in LETO at 40 and 60 weeks, suggesting that increase of PAI-1 may downregulate compensatory adaptive capillary network remodeling by inhibiting proteolysis and angiogenesis in the cardiac interstitium. Loss of adaptive myocardial microcirculation may therefore contribute to increased vulnerability in ischemic injury and to cardiac dysfunction in NIDDM.

Animals↗
PubMed2003

Increased expression of plasminogen activator inhibitor-1 by mediators of the acute phase response: a potential progenitor of vasculopathy in hypertensives.

Hypertension is an important risk factor for coronary atherosclerosis, which is accelerated by inflammation and diminished fibrinolysis. We have previously shown that levels of plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of fibrinolysis, are increased with atherogenic metabolic derangement. Because the liver is one of the major sources of circulating PAI-1, we here examined the effects of two proinflammatory cytokines, interleukin (IL)-1beta, and IL-6, on PAI-1 production in a human hepatoma cell line, HepG2. IL-1beta (1 ng/ml) and IL-6 (1 ng/ml) increased the accumulation of PAI-1 in the conditioned media over 24 h (IL-1beta: 2.1 +/- 0.2 (mean +/- SD) fold over the control; IL-6:1.4 +/- 0.2 fold; Western blot, p < 0.05). The increase in PAI-1 protein accumulation correlated with the increased expression of PAI-1 mRNA (Northern blot). An HMG-CoA reductase inhibitor (mevastatin, 10 micromol/l) attenuated the PAI-1 production induced by IL-1beta and IL-6. The plasma PAI-1 activity level was higher in hypertensives than in normotensives (10.0 +/- 9.8 AU/ml vs. 6.2 +/- 4.5 AU/ml, p < 0.05). The plasma PAI-1 antigen level was also higher in hypertensives than in normotensives (30.9 +/- 22.4 ng/ml vs. 24.4 +/- 13.3 ng/ml, p < 0.05). Thus, 1) IL-1beta and IL-6 can increase PAI-1 production in hepatic cells and 2) mevastatin may exert anti-thrombotic effects by decreasing the PAI-1 protein production induced by these proinflammatory cytokines. These results provide further insights into how inflammation is involved in the atherothrombotic complications observed in hypertensives, which may be ameliorated by HMG-CoA reductase inhibitors.

Acute-Phase Reaction↗
PubMed2003

Low expression levels of soluble CD1d gene in patients with rheumatoid arthritis.

OBJECTIVE: To examine whether the expression of intact CD1d, a critical molecule for the presentation of glycolipid antigens to natural killer T (NKT) cells, and its variants differs between patients with autoimmune diseases including rheumatoid arthritis (RA) and healthy subjects. Recently, we identified 8 different CD1d variants, generated by alternative splicing. V1 lacking exon 4 (CD1d without beta2 microglobulin, beta2m) and V2 lacking exons 4 and 5 (soluble CD1d) may be functional molecules, because the antigen binding sites (exons 2 and 3) are intact. METHODS: Peripheral blood mononuclear cells (PBMC) from 44 patients with autoimmune disease (RA 19, systemic lupus erythematosus, SLE 10, Sjögren's syndrome, SS 15) and 15 healthy controls were separated and complementary (c)DNA was prepared. The expression of intact CD1d on PBMC was detected by flow cytometry. Alternatively spliced CD1d variants were quantified by TaqMan PCR using polymerase chain reaction with confronting 2-pair primers (PCR-CTPP) based amplification. RESULTS: The mean (+/- SEM) transmembrane and beta2m binding site deleted CD1d mRNA level in 19 patients with RA (2.0 +/- 0.33) was significantly lower than in 15 controls (6.9 +/- 2.08; p < 0.05), whereas there were no differences in beta2m deleted variants and intact CD1d mRNA. CONCLUSION: Our findings suggest that low expression of soluble CD1d variants might play a role in the formation of symptoms or pathogenesis of RA.

Alternative Splicing↗
PubMed2002

Induction of plasminogen activator inhibitor-1 in endothelial cells by basic fibroblast growth factor and its modulation by fibric acid.

Plasminogen activator inhibitor-1 (PAI-1) inhibits fibrinolysis and proteolysis. Basic fibroblast growth factor (bFGF) stimulates angiogenesis, which requires regional proteolysis. Because modulation of vasculopathy requires tight control of proteolysis, effects of bFGF on PAI-1 expression in endothelial cells (ECs) were characterized. bFGF increased PAI-1 mRNA and accumulation of PAI-1 protein in conditioned media in human umbilical vein ECs. The bFGF-mediated increase in PAI-1 mRNA was attenuated by inhibition of extracellular signal-regulated kinase kinase in human ECV304 cells. The rate of decrease in PAI-1 mRNA after actinomycin D treatment was not affected by bFGF. Transient transfection assays of the human PAI-1 promoter-luciferase construct demonstrated that bFGF-induced PAI-1 transcription was dependent on the elements within the -313 to -260 bp relative to the transcription start site. This region contains an E26 transformation specific 1 (Ets-1)-like site. Electrophoretic mobility shift assay showed that bFGF increased nuclear translocation or DNA binding of the Ets-1-like transcription factor to the PAI-1 promoter. Nucleotide substitution to disrupt the Ets-1-like site reduced bFGF-stimulated promoter activity. Fenofibric acid, an agonist ligand for the peroxisome proliferator-activated receptor-alpha, inhibited basal and bFGF-stimulated PAI-1 expression. By inducing PAI-1 expression from ECs, bFGF may control proteolysis and fibrinolysis in vessel walls.

5' Flanking Region↗
PubMed2002

Islet hyperperfusion during prediabetic phase in OLETF rats, a model of type 2 diabetes.

Although it has been hypothesized that initial hyperperfusion followed by late hypoperfusion in islet circulation occurs in rodent models of type 2 diabetes, islet blood flow has not been measured during prediabetic phase. We studied islet blood flow in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of slowly progressive obese type 2 diabetes. Islet blood flow was measured by the two-color microsphere method under anesthesia at different ages. Islet blood flow was significantly higher in young OLETF rats compared with control Long-Evans Tokushima Otsuka (LETO) rats when the former were not obese or diabetic and had normal insulin secretion at 5 weeks of age (LETO 4.6 +/- 1.1, OLETF 8.8 +/- 1.2 ml. min(-1). mg(- 1), P < 0.01). At 6 months of age, islet hyperperfusion was observed in OLETF rats, and >40% of whole pancreatic blood flow was diverted into islets in OLETF rats. Prevention of obesity by food restriction increased basal islet blood flow. On the other hand, long-term hyperglycemia induced by sucrose feeding decreased fractional islet blood flow as well as glucose-stimulated islet blood flow. Our results indicate that hyperperfusion is present during the preobese and prediabetic phase in our type 2 diabetes rats.

Animals↗