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Biomedical subjects

Toru Kita

Publications and source records attributed to Toru Kita.

At least 109 records · Page 6Linked to original sources
PubMed2004

Chemokines generally exhibit scavenger receptor activity through their receptor-binding domain.

Chemokines are a family of cytokines that induce directed migration of various types of leukocytes through specific interactions with a group of seven transmembrane receptors. Scavenger receptors are a heterogenous family of transmembrane molecules that commonly bind and uptake oxidized low density lipoprotein and bacteria. Here, we show that not only CXC chemokine 16 (CXCL16)/SR-PSOX, a transmembrane chemokine with scavenger receptor activity, but also 12 out of 15 chemokines examined efficiently bound scavenger receptor ligands in competition with cells expressing their specific chemokine receptors. Furthermore both the chemotactic and scavenger receptor activities of SR-PSOX/CXCL16 were similarly impaired in a series of mutants altered in the chemokine domain, indicating that SR-PSOX/CXCL16 binds scavenger receptor ligands as well as CXCR6 using highly overlapping binding motifs. Taken together, chemokines generally have scavenger receptor-like activity through their receptor-binding domain, suggesting a close evolutionary relationship between chemokines and scavenger receptors.

Amino Acid Substitution↗
PubMed2004

Endothelin-1-dependent nuclear factor of activated T lymphocyte signaling associates with transcriptional coactivator p300 in the activation of the B cell leukemia-2 promoter in cardiac myocytes.

Endothelin-1 (ET-1) is a potent survival factor that protects cardiac myocytes from apoptosis. ET-1 induces cardiac gene transcription and protein expression of antiapoptotic B cell leukemia-2 (bcl-2) in a calcineurin-dependent manner. A cellular target of adenovirus early region 1A (E1A) oncoprotein, p300 also activates bcl-2 transcription in cardiac myocytes and is required for their survival. p300 acts as a calcineurin-regulated nuclear factors of activated T lymphocytes (NFATc), downstream targets of calcineurin. In addition, the bcl-2 promoter contains multiple NFAT consensus sequences. These findings prompted us to investigate the role of NFATc in ET-1-dependent and p300-dependent bcl-2 transcription in cardiac myocytes. In primary cardiac myocytes prepared from neonatal rats, mutation of 2 NFAT sites within the bcl-2 promoter completely abolished the ET-1- and p300-induced increases in the activity of this promoter. We show here that p300 markedly potentiates the binding of NFATc1 to the bcl-2 NFAT element by interacting with NFATc1 in an E1A-dependent manner. On the other hand, stimulation of cardiac myocytes with ET-1 causes nuclear translocation of NFATc1, which interacts with p300 and increases DNA binding. Expression of E1A did not change the cardiac nuclear localization of NFATc1 but blocked its interaction with p300, DNA binding, and bcl-2 promoter activation. These findings suggest that ET-1-dependent NFATc signaling associates with p300 in the transactivation of bcl-2 gene in cardiac myocytes.

Animals↗
PubMed2004

Antigenic activation of Th1 cells in the gastric mucosa enhances dysregulated apoptosis and turnover of the epithelial cells.

Colonization of Helicobacter pylori in the stomach leads to chronic gastritis with massive infiltration by Th1 cells. To assess a role played by those T cells in the remodeling of gastric epithelium, we activated gastric T cells utilizing mice with CD4 T cells bearing transgenic TCR with or without deficiency in either IL-4 or IFN-gamma or IL-12. Mice developed gastritis upon injection of an antigen into gastric mucosa. While neutrophil infiltration occurred even with a control antigen, infiltration by transgenic T cells was dependent on the specific antigen. The numbers of epithelial cells undergoing apoptosis and regeneration were increased in the mice with infiltrating T cells producing IFN-gamma and the alignment of those cells in the glands was markedly dysregulated. In contrast, mice deficient in Th1 response showed no increase in cell division and apoptosis of epithelial cells. Thus, Th1 type T cells infiltrating into gastric mucosa play an independent role in controlling turnover of epithelial cells.

Animals↗
PubMed2004

Expression of p300 protects cardiac myocytes from apoptosis in vivo.

Doxorubicin is an anti-tumor agent that represses cardiac-specific gene expression and induces myocardial cell apoptosis. Doxorubicin depletes cardiac p300, a transcriptional coactivator that is required for the maintenance of the differentiated phenotype of cardiac myocytes. However, the role of p300 in protection against doxorubicin-induced apoptosis is unknown. Transgenic mice overexpressing p300 in the heart and wild-type mice were subjected to doxorubicin treatment. Compared with wild-type mice, transgenic mice exhibited higher survival rate as well as more preserved left ventricular function and cardiac expression of alpha-sarcomeric actin. Doxorubicin induced myocardial cell apoptosis in wild-type mice but not in transgenic mice. Expression of p300 increased the cardiac level of bcl-2 and mdm-2, but not that of p53 or other members of the bcl-2 family. These findings demonstrate that overexpression of p300 protects cardiac myocytes from doxorubicin-induced apoptosis and reduces the extent of acute heart failure in adult mice in vivo.

Actins↗
PubMed2004

Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy.

Advanced glycation end products (AGEs) appear to contribute to the diabetic complications. This study reports the inhibitory effect of OPB-9195 (OPB), an inhibitor of AGEs formation, and the role of a collagen-specific molecular chaperone, a 47-kDa heat shock protein (HSP47) in diabetic nephropathy. Transgenic mice carrying nitric-oxide synthase cDNA fused with insulin promoter (iNOSTg) leads to diabetes mellitus. The iNOSTg mice at 6 months of age represented diffuse glomerulosclerosis, and the expression of HSP47 was markedly increased in the mesangial area in parallel with increased expression of types I and IV collagens. OPB treatment ameliorated glomerulosclerosis in the iNOSTg mice associated with the decreased expression of HSP47 and types I and IV collagens. The expression of transforming growth factor-beta (TGF-beta) was increased in glomeruli of iNOSTg mice and decreased after treatment with OPB. To confirm these mechanisms, cultured mesangial cells were stimulated with AGEs. AGEs significantly increased the expression of HSP47, type IV collagen, and TGF-beta mRNA. Neutralizing antibody for TGF-beta inhibited the overexpression of both HSP47 and type IV collagen in vitro. In conclusion, AGEs increase the expression of HSP47 in association with collagens, both in vivo and in vitro. The processes may be mediated by TGF-beta.

Animals↗
PubMed2004

Role of bone marrow-derived progenitor cells in cuff-induced vascular injury in mice.

OBJECTIVE: Arterial injury results in vascular remodeling associated with proliferation and migration of smooth muscle cells (SMCs) and the development of intimal hyperplasia, which is a critical component of restenosis after angioplasty of human coronary arteries and an important feature of atherosclerotic lesions. However, the origin of SMCs and other cells in the development of vascular remodeling is not yet fully understood. METHODS AND RESULTS: We utilized a cuff-induced vascular injury model after transplantation of the bone marrow (BM) from green fluorescent protein (GFP)-transgenic mice. We found that macrophages were major cells recruited to the adventitia of the vascular injury lesion along with SMCs and endothelial cells (ECs). While investigating whether those cells are derived from the donor, we found that most of the macrophages were GFP-positive, and some of the SMCs and ECs were also GFP-positive. Administration of the anti-c-fms antibody resulted in a marked decrease in macrophages and a relative increase of SMCs, while administration of antibodies against the platelet-derived growth factor receptor-beta caused a prominent decrease in SMCs and a relative increase in macrophages. CONCLUSIONS: The current study indicates that BM-derived cells play an important role in vascular injury, and that differentiation of macrophages and SMCs might be dependent on each other.

Animals↗
PubMed2004

Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation.

Prolonged exposure to hyperglycemia is now recognized as the most significant causal factor of diabetic complications. Excessive advanced glycation end products (AGEs) as a result of hyperglycemia in tissues or in the circulation may critically affect the progression of diabetic nephropathy. In diabetic nephropathy, glomerulosclerosis is a typical pathologic feature characterized by the increase of the extracellular matrix (ECM). We have reported previously that alpha1 type IV collagen (Col4) is one of the major components of ECM, which is up-regulated by AGEs, and that the overexpression of Col4 is transcriptionally regulated by an unknown transcription factor binding to the promoter. Here we identified this protein as Smad1 by yeast one-hybrid screening. Using chromatin immunoprecipitation and reporter assay, we observed that Smad1 directly regulated transcription for Col4 through the binding of Smad1 to the promoter of Col4. Smad1 was significantly induced along with Col4 in AGE-treated mesangial cells. Moreover, suppression of Smad1 by antisense morpholino resulted in a decrease of AGE-induced Col4 overproduction. To elucidate the interaction between transforming growth factor-beta and Smad1, we investigated whether activin receptor-liked kinase1 (ALK1) was involved in this regulation. AGE stimulation significantly increased the expression of the ALK1 mRNA in mesangial cells. We also demonstrated that Smad1 and ALK1 were highly expressed in human diabetic nephropathy. These results suggest that the modulation of Smad1 expression is responsible for the initiation and progression of diabetic nephropathy and that blocking Smad1 signaling may be beneficial in preventing diabetic nephropathy and other various diabetic complications.

Activin Receptors, Type I↗
PubMed2004

Quantitative trait loci (QTL) analysis reveals a close linkage between the hinge region and trimeric IgA dominancy in a high IgA strain (HIGA) of ddY mice.

Polymerization of IgA has been suggested as one of the causes of mesangial deposition in IgA nephropathy. HIGA mice are an inbred model of IgA nephropathy, established by selective mating of ddY mice. This strain is characterized by a unique profile of the IgA molecule that is dominantly polymeric and has high serum levels with intense IgA deposition on the mesangium. We carried out quantitative trait loci (QTL) analysis, using F2 generations by crossing HIGA with BALB/c mice. Significant linkage of polymeric IgA in serum samples was identified around D12Mit263, which is close to the gene of the immunoglobulin heavy chain on chromosome 12. The amino acid sequence of the alpha heavy chain revealed marked differences between BALB/c and HIGA mice. Furthermore, most differences were focussed on the hinge region. The DBA/2J strain, which has the same amino acid sequence in the hinge region as the HIGA strain, also showed polymeric IgA dominance but low IgA levels in sera. Size fraction analysis revealed that these polymeric IgA showed trimer dominance in both DBA/2J and HIGA mice. In conclusion, the hinge region plays a key role in trimeric IgA formation in HIGA mice.

Amino Acid Sequence↗
PubMed2004

Role of mesangial Factor V expression in crescent formation in rat experimental mesangioproliferative glomerulonephritis.

It has been suggested that fibrin deposition participates in the development of crescents in active glomerulonephritis (GN). In human IgA nephropathy, which is a common form of mesangioproliferative GN (MsPGN), crescent formation is occasionally observed in active disease, leading to end-stage renal failure. Factor V is a membrane-bound potent cofactor for the conversion of prothrombin to thrombin by Factor Xa. An in vivo study was conducted to clarify the contribution of local fibrin production to crescent formation in MsPGN through mesangial Factor V expression. Wistar rats were injected intravenously with rabbit anti-rat thymocyte serum. Three days after injection, mesangiolysis with intense mesangial Factor V expression was observed and immunoelectron microscopy revealed fibrin localization in mesangiolytic lesions, which had spread into the glomerular basement membrane adjacent to the destroyed mesangium, accompanied by clots in Bowman's space. Marked glomerular fibrin deposition, together with its deposition in Bowman's space and cellular crescent formation, was noted with mesangial proliferation on day 8. Specific bands for Factor V mRNA were also detected from isolated glomeruli. Fibrin deposition and cellular crescent formation were significantly suppressed by treatment with anti-Factor V antibody. These results suggest that local fibrin production, following mesangial Factor V expression, together with mesangiolysis that spreads to the adjacent glomerular basement membrane, plays a role in crescent formation in MsPGN.

Animals↗
PubMed2004

Suppressive effects of Sairei-to on mesangial proliferation in a rat model of glomerulonephritis.

BACKGROUND: Sairei-to (TJ-114) is a Japanese herbal medicine of standardized quality, originating from traditional Chinese medicine. In the present in vivo study, we investigated the suppressive effects of TJ-114, Shosaiko-to (TJ-9), and Saiboku-to (TJ-96) on mesangioproliferative glomerulonephritis (MsPGN) in rats. We evaluated the efficacy of these drugs on proteinuria, mesangial cell proliferation, and superoxide dismutase (SOD) activity. METHODS: MsPGN was induced in Wistar rats by intravenous injection of rabbit anti-rat thymocyte serum (ATS). TJ-114, TJ-9, or TJ-96 (500 mg/kg per day) was orally administered to the rats in drinking water from the day of ATS injection (day 0) to day 8, when rats were killed and kidney specimens were collected. The degree of mesangial cell proliferation was evaluated by immunostaining for proliferating cell nuclear antigen (PCNA) or macrophage antigen (ED-1). SOD activity in the homogenate of the renal cortex was also evaluated. RESULTS: The amount of urinary albumin was significantly decreased only in the TJ-114-treated group compared with the disease control group ( P < 0.05). The number of PCNA- or ED-1-positive cells was significantly decreased in all the treatment groups ( P < 0.05, respectively, compared with the disease control group). SOD activity in the renal cortex homogenate was significantly augmented in all the treatment groups, most markedly in the TJ-96- and TJ-114-treated groups ( P < 0.01, respectively, compared with the disease control group). CONCLUSIONS: These results suggest that TJ-114 suppresses the proliferation of mesangial cells through its antioxidative activity.

Animals↗
PubMed2004

Heparin-binding EGF-like growth factor induces expression of lectin-like oxidized LDL receptor-1 in vascular smooth muscle cells.

Receptor-mediated endocytosis of oxidized LDL (Ox-LDL) has been implicated in lipid accumulation and vascular cell dysfunction. Lectin-like Ox-LDL receptor-1 (LOX-1) is highly inducible by proinflammatory cytokines, as well as angiotensin II and Ox-LDL in vitro. LOX-1 is expressed in macrophages and smooth muscle cells accumulated in the intima of advanced atherosclerotic plaques in vivo. Here we show that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent mitogen for vascular smooth muscle cells, induces LOX-1 expression in cultured bovine aortic smooth muscle cells. HB-EGF (1-100 ng/ml) induced LOX-1 expression, which was peaked between 8 and 16 h after HB-EGF stimulation. HB-EGF-induced expression of LOX-1 was suppressed by ZD1839, an inhibitor of EGF receptor phosphorylation. Both MEK and p38 mitogen-activated protein kinase (MAPK) inhibitors significantly blocked LOX-1 upregulation induced by HB-EGF. Phosphatidylinositol 3-kinase (PI3K) inhibitors also blocked HB-EGF-induced LOX-1 expression. HB-EGF induced phosphorylation of ERK, p38 MAPK and Akt, which were suppressed by ZD1839. Upregulated expression of LOX-1 was associated with enhanced uptake of DiI-labeled Ox-LDL in smooth muscle cells. Taken together, HB-EGF can also act as an inducer of LOX-1 expression and play an integral role in foam cell transformation, cellular dysfunction, and proliferation of smooth muscle cells in atherogenesis.

Animals↗
PubMed2004

Successful endovascular repair of an aneurysm of the ductus diverticulum with a branched stent graft: case report and review of literature.

Aneurysm of the ductus diverticulum rarely has been reported in adults, and the reported aneurysms were treated with conventional open surgery or were diagnosed at autopsy. We report a successful endovascular repair of an aneurysm of the ductus diverticulum with the Inoue branched stent graft. In a 78-year-old woman, an abnormal shadow was noted at the aortopulmonary window on a chest x-ray film. A computed tomography scan demonstrated a 3.8-cm saccular aneurysm, which protruded inferiorly from the distal end of the aortic arch. The aneurysm was considered an aneurysm of the ductus diverticulum, and surgery was required. However, the patient was considered at high risk for respiratory dysfunction with conventional open surgery. Endovascular repair with an Inoue single-branched stent graft was performed with the patient under local anesthesia, successfully and without complication or endoleak. To our knowledge, this is the first report of endovascular treatment of an aneurysm of the ductus diverticulum.

Aged↗
PubMed2004

Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome.

INTRODUCTION: Beta-blockers are widely used to prevent the lethal cardiac events associated with the long QT syndrome (LQTS), especially in KCNQ1-related LQTS (LQT1) patients. Some LQT1 patients, however, are refractory to this therapy. METHODS AND RESULTS: Eighteen symptomatic LQTS patients (12 families) were genetically diagnosed as having heterozygous KCNQ1 variants and received beta-blocker therapy. Cardiac events recurred in 4 members (3 families) despite continued therapy during mean follow-up of 70 months. Three of these patients (2 families) had the same mutation [A341V (KCNQ1)]; and the other had R243H (KCNQ1). The latter patient took aprindine, which seemed to be responsible for the event. By functional assay using a heterologous mammalian expression system, we found that A341V (KCNQ1) is a loss-of-function type mutation (not dominant negative). Further genetic screening revealed that one A341V (KCNQ1) family cosegregated with S706C (KCNH2) and another with G144S (KCNJ2). Functional assay of the S706C (KCNH2) mutation was found to reduce the current density of expressed heterozygous KCNH2 channels with a positive shift (+8 mV) of the activation curve. Action potential simulation study was conducted based on the KYOTO model to estimate the influence of additional gene modifiers. In both models mimicking LQT1 plus 2 and LQT1 plus 7, the incidence of early afterdepolarization was increased compared with the LQT1 model under the setting of beta-adrenergic stimulation. CONCLUSION: Multiple mutations in different LQTS-related genes may modify clinical characteristics. Expanded gene survey may be required in LQT1 patients who are resistant to beta-blocker therapy.

Action Potentials↗
PubMed2004

Primary cardiovascular events and serum lipid levels in elderly Japanese with hypercholesterolemia undergoing 6-year simvastatin treatment: a subanalysis of the Japan lipid intervention trial.

OBJECTIVES: To determine the relationship between serum lipid levels and the incidence of coronary events in older Japanese hypercholesterolemic patients without prior coronary heart disease (CHD). DESIGN: Post hoc subanalysis of the results in the Japan Lipid Intervention Trial. SETTING: A large-scale cohort observational study conducted throughout Japan. PARTICIPANTS: Men aged 35 to 70 and postmenopausal women younger than 70 with serum total cholesterol (TC) level of 220 mg/dL or greater treated for 6 years with low-dose simvastatin (52,421 total patients). After exclusion of 5,127 patients because of prior CHD and 4,934 patients because of incomplete data, 42,360 patients were divided into an older (9,860 patients, aged 65-70, mean age 67.1) and younger (32,500 patients, younger than 65, mean age 54.9) group and analyzed. MEASUREMENTS: Fasting serum lipid levels were measured every 6 months. Major coronary events, including fatal or nonfatal myocardial infarction, and sudden cardiac death as the primary endpoint and other cardiovascular diseases, including onset of angina pectoris, cerebrovascular events, and any causes of death, as the secondary endpoints were monitored. RESULTS: Simvastatin treatment in older patients was as safe and effective as in younger patients. Incident rates of major coronary events were 1.30 per 1,000 patient-years in the older group and 0.80 per 1,000 patient-years in the younger group. The incidence of a major coronary event was correlated to serum TC and low-density lipoprotein cholesterol (LDL-C) levels in both groups. The absolute risk of major coronary events in the older group was higher than in the younger group at any level of LDL-C, whereas the relative risk increased by 1.7% with an elevation of each 1 mg/dL LDL-C level in both groups. In the older group, the risk of major coronary events also increased as triglyceride level increased, whereas the risk decreased as high-density lipoprotein cholesterol level increased above 60 md/dL. CONCLUSION: The LDL-C level-dependent increase of relative risk of CHD was similar in elderly and younger patients, whereas the absolute risk at any LDL-C level in elderly patients was higher than in younger patients.

Adult↗
PubMed2004

Role of Hand1/eHAND in the dorso-ventral patterning and interventricular septum formation in the embryonic heart.

Molecular mechanisms for the dorso-ventral patterning and interventricular septum formation in the embryonic heart are unknown. To investigate a role of Hand1/eHAND in cardiac chamber formation, we generated Hand1/eHAND knock-in mice where Hand1/eHAND cDNA was placed under the control of the MLC2V promoter. In Hand1/eHAND knock-in mice, the outer curvature of the right and left ventricles expanded more markedly. Moreover, there was no interventricular groove or septum formation, although molecularly, Hand1/eHAND knock-in hearts had two ventricles. However, the morphology of the inner curvature of the ventricles, the atrioventricular canal, and the outflow tract was not affected by Hand1/eHAND expression. Furthermore, expression of Hand1/eHAND in the whole ventricles altered the expression patterns of Chisel, ANF, and Hand2/dHAND but did not affect Tbx5 expression. In contrast, the interventricular septum formed normally in transgenic embryos overexpressing Hand1/eHAND in the right ventricle but not in the boundary region. These results suggested that Hand1/eHAND is involved in expansion of the ventricular walls and that absence of Hand1/eHAND expression in the boundary region between the right and left ventricles may be critical in the proper formation of the interventricular groove and septum. Furthermore, Hand1/eHAND is not a master regulatory gene that specifies the left ventricle myocyte lineage but may control the dorso-ventral patterning in concert with additional genes.

Animals↗
PubMed2004

Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice.

Production of thromboxane (TX) A2 and PG I2/prostacyclin (PGI2) is increased in patients with atherosclerosis. However, their roles in atherogenesis have not been critically defined. To examine this issue, we cross-bred atherosclerosis-prone apoE-deficient mice with mice deficient in either the TXA receptor (TP) or the PGI receptor (IP). Although they showed levels of serum cholesterol and triglyceride similar to those of apoE-deficient mice, apoE-/-TP-/- mice exhibited a significant delay in atherogenesis, and apoE-/-IP-/- mice exhibited a significant acceleration in atherogenesis compared with mice deficient in apoE alone. The plaques in apoE-/-IP-/- mice showed partial endothelial disruption and exhibited enhanced expression of ICAM-1 and decreased expression of platelet endothelial cell adhesion molecule 1 (PECAM-1) in the overlying endothelial cells compared with those of apoE-/-TP-/- mice. Platelet activation with thrombin ex vivo revealed higher and lower sensitivity for surface P-selectin expression in platelets of apoE-/-IP-/- and apoE-/-TP-/- mice, respectively, than in those of apoE-/- mice. Intravital microscopy of the common carotid artery revealed a significantly greater number of leukocytes rolling on the vessel walls in apoE-/-IP-/- mice than in either apoE-/-TP-/- or apoE-/- mice. We conclude that TXA2 promotes and PGI2 prevents the initiation and progression of atherogenesis through control of platelet activation and leukocyte-endothelial cell interaction.

Animals↗
PubMed2004

Combined measurements of cardiac troponin T and N-terminal pro-brain natriuretic peptide in patients with heart failure.

BACKGROUND: To examine the prognostic contribution of combined cardiac troponin T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with heart failure (CHF) in the absence of acute coronary syndrome. METHODS AND RESULTS: Between July 2001 and March 2002, 71 consecutive patients (mean age = 68.4+/-1.4 years, 37 men), hospitalised for heart failure, were studied during hospitalisation and follow up until December 2002. Serum cTnT and NT-proBNP were measured on admission. Actuarial rates of adverse cardiac events, including sudden or CHF death, or rehospitalisation for CHF during follow up were compared with patients grouped according to initial serum cTnT and/or NT-proBNP concentrations. The adverse cardiac event-free rate among the 20 patients with cTnT > or 0.01 ng/ml was significantly lower than the 51 patients with cTnT <0.01 ng/ml (P<0.05). Similarly, the adverse cardiac event-free rate among the 36 patients with NT-proBNP > or =1,357 pg/ml (median) was significantly lower than the 35 patients with NT-proBNP <1,357 pg/ml (P<0.01). The 16 patients with high concentrations of both cTnT and NT-proBNP had a lower adverse cardiac event-free rate than the 31 patients with low cTnT and low NT-proBNP upon commencement of the study (P<0.005). CONCLUSION: Measurements of serum cTnT and NT-proBNP were reliable prognostic markers of adverse cardiac event in patients with CHF.

Aged↗