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Y Tsurumi

Publications and source records attributed to Y Tsurumi.

At least 37 records · Page 2Linked to original sources
PubMed1996

Accelerated restitution of endothelial integrity and endothelium-dependent function after phVEGF165 gene transfer.

BACKGROUND: Delinquent reendothelialization (rET) has been shown to have a permissive, if not facilitatory, impact on smooth muscle cell proliferation. This inverse relation has been attributed to certain functions of the endothelium, including barrier regulation of permeability, thrombogenicity, and leukocyte adherence, as well as production of growth-inhibitory molecules. Accordingly, the present investigation was designed to test the hypothesis that an endothelial cell (EC) mitogen could serve as the basis for a novel gene therapy strategy designed to facilitate EC regeneration, reduce neointimal thickening, and promote recovery of EC dysfunction after balloon injury. METHODS AND RESULTS: New Zealand White rabbits underwent simultaneous balloon injury and gene transfer of one femoral artery with phVEGF165, encoding the 165-amino acid isoform of vascular endothelial growth factor (VEGF), or pGSVLacZ. In each animal transfected with phVEGF165 or pGSVLacZ, the contralateral femoral artery was also subjected to balloon injury but not to gene transfer. For pGSVLacZ, rET remained incomplete at 4 weeks after transfection; in contrast, phVEGF165 produced prompt rET, which was 95% complete by 1 week. Furthermore, rET in the contralateral, balloon-injured, nontransfected limb of the VEGF group was similarly accelerated. Consequently, intimal thickening was diminished, thrombotic occlusion was less frequent, and recovery of EC-dependent vasomotor reactivity was accelerated in VEGF transfectants compared with control animals. A similar benefit was observed for the contralateral, balloon-injured, nontransfected limb. CONCLUSIONS: Catheter-mediated, site-specific arterial gene transfer of phVEGF165 can accelerate rET at local and remote sites, leading to inhibition of neointimal thickening, reduction in thrombogenicity, and restoration of endothelium-dependent vasomotor reactivity. These findings support the notion that gene transfer encoding for an EC-specific mitogen may be useful for preventing the complications, including restenosis, of balloon angioplasty.

Angioplasty, Balloon↗
PubMed1996

The in vivo bioactivity of vascular endothelial growth factor/vascular permeability factor is independent of N-linked glycosylation.

The carbohydrate moieties of glycoprotein hormones or growth factor molecules may have a variety of effects that impact biological potency. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a 45 kD heparin-binding, endothelial cell (EC) specific mitogen with a putative N-linked glycosylation site. Recent studies have shown that VEGF/VPF may successfully augment collateral development in animal models of myocardial and hindlimb ischemia. The extent to which glycosylation of the 75 asparagine site affects the angiogenic properties of VEGF/VPF has not been studied in vivo. Specifically unaddressed to date is the concern that nonglycosylated VEGF/VPF may be less stable, and therefore characterized by a shorter half-life, reducing its utility for therapeutic angiogenesis. Accordingly, the purpose of this study was to investigate the extent to which posttranslational modification, specifically glycosylation, mofies the angiogenic properties of VEGF/VPF in vivo. Glycosylated (g+) recombinant human VEGF165 was purified from media conditioned by Chinese hamster ovary (CHO) cells. Nonglycosylated (g-) VEGF165 was expressed, purified and refolded from E. coli. The purity of both materials was assessed by silver-stained SDS/PAGE and characterized by the presence of a single amino terminal sequence as indicated by Edman degradation. Tryptic mapping by reverse-phase HPLC confirmed that the potential glycosylation site at 75 asparagine was occupied by N-linked carbohydrate for the Chinese hamster ovary-derived VEGF/VPF, but not for E. coli-derived VEGF/VPF. The mitogenic effects of Chinese hamster ovary-derived (g+) VEGF165 and E. coli-derived (g-) VEGF165 wre studied in vitro using microvascular EC. At concentrations of VEGF/VPF ranging from 10(-4) to 10(2) nM, both produced similar concentration-dependent effects on EC proliferation. For in vivo studies, (g-) (n = 8) and (g+) (n = 8) formulations of VEGF/VPF were administered to New Zealand white rabbits with unilateral hindlimb ischemia. For (g-) versus (g+) VEGF/VPF-treated groups, respectively, calf blood pressure ratio was 0.40 +/- 0.04 versus 0.37 +/- 0.04; angiographic score (of collateral vessels) was 0.37 +/- 0.04 versus 0.35 +/- 0.04; capillary density (capillaries/mm2) at necropsy was 246.9 +/- 21.5 versus 253.9 +/- 18.8; and tissue perfusion (colored microspheres) was 92.8 +/- 5.5 versus 90.30 +/- 13.47 (all p = ns). Moreover, intravascular Doppler-based analyses of resting, maximum, and endothelium-dependent flow was similar for (g-) and (g+) VEGF/VPF. These in vitro and in vivo findings establish that the potential for VEGF/VPF to stimulate therapeutic angiogenesis persists unaltered in the nonglycosylated state.

Angiography↗
PubMed1996

Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo.

Vascular endothelial growth factor (VEGF) is a naturally secreted endothelial cell-specific mitogen. We investigated the hypothesis that naked DNA encoding for VEGF could be used in a strategy of arterial gene therapy to stimulate collateral artery development. Plasmid DNA encoding each of the three principal human VEGF isoforms (phVEGF121, phVEGF165, or phVEGF189) was applied to the hydrogel polymer coating of an angioplasty balloon and delivered percutaneously to one iliac artery of rabbits with operatively induced hindlimb ischemia. Compared with control animals transfected with LacZ, site-specific transfection of phVEGF resulted in augmented collateral vessel development documented by serial angiography, and improvement in calf blood pressure ratio (ischemic to normal limb), resting and maximum blood flow, and capillary to myocyte ratio. Similar results were obtained with phVEGF121, phVEGF165, and phVEGF189, which suggests that these isoforms are biologically equivalent with respect to in vivo angiogenesis. The fact that viral or other adjunctive vectors were not required further suggests that secreted gene products may have potential therapeutic utility even when the number of successfully transfected cells remains low. Arterial gene transfer of naked DNA encoding for a secreted angiogenic cytokine, thus, represents a potential alternative to recombinant protein administration for stimulating collateral vessel development.

Animals↗
PubMed1996

Naked cDNA encoding secreted proteins for intra-arterial and intramuscular gene transfer.

Experience with intra-arterial and intramuscular gene transfer of VEGF illustrates in prototypical fashion how features of the gene, protein, and target tissue may all contribute to phenotypic modulation of the host despite the low transfection efficiency typical of naked plasmid DNA. These features include the fact that VEGF is naturally secreted, binds to cell-surface heparan sulfates, is generated by hypoxic endothelial cells, reduces apoptosis, and binds to high-affinity receptors that are upregulated by hypoxia. Thus the success of gene therapy is not solely a function of vectors or transfection efficiency.

Animals↗
PubMed1995

Influence of plasma lipoprotein (a) levels on coronary vasomotor response to acetylcholine.

OBJECTIVES: This study was undertaken to examine the influence of plasma lipoprotein(a) [Lp(a)] levels on coronary endothelial vasomotor function. BACKGROUND: Epidemiologic studies have demonstrated a direct relation between elevated plasma levels of Lp(a) and increased risk of coronary artery disease. Well recognized coronary risk factors are known to affect endothelium-dependent vasomotion; however, the influence of Lp(a) on coronary vasomotor function has not been determined. METHODS: We used quantitative coronary angiography to measure left anterior descending coronary artery diameter changes produced by intracoronary acetylcholine and isosorbide dinitrate in 30 patients with angiographically normal coronary arteries. Plasma Lp(a) levels were determined with enzyme-linked immunosorbent assay. RESULTS: Vasomotor response to acetylcholine ranged from +13% to -47% in the proximal, from +23% to -53% in the middle and from +13% to -56% in the distal segment of the left anterior descending coronary artery. According to univariate linear regression analysis, Lp(a) had a significant inverse correlation with vasomotor response to acetylcholine: r = 0.47, p < 0.01 in the proximal; r = -0.61, p < 0.001 in the middle; and r = -0.52, p < 0.01 in the distal segment of the left anterior descending coronary artery. By multiple stepwise regression analysis, plasma Lp(a) was the significant predictor of vasomotion in response to acetylcholine in all tested segments (p < 0.01). CONCLUSIONS: Elevated Lp(a) levels were associated with impairment of endothelium-dependent vasodilation even when atherosclerotic lesions were not recognizable by angiography. This finding suggests that elevated plasma levels of Lp(a) cause endothelial dysfunction and may contribute in part to later development of atherosclerosis, as shown in epidemiologic studies.

Acetylcholine↗
PubMed1995

Clinical application of 18F-FUdR in glioma patients--PET study of nucleic acid metabolism.

Positron emission tomography was used to investigate the metabolism of nucleic acids by 18F-fluoro-2'-deoxyuridine (18F-FUdR) in 22 patients with gliomas. Sixteen cases of high grade glioma clearly demonstrated a region of high activity with a differential absorption rate (DAR) of 0.64 +/- 0.34. Six cases of low grade glioma failed to reveal a positive image of the tumor and the DAR in tumor was 0.21 +/- 0.042 (p < 0.01). This PET-18F-FUdR study succeeded in differentiating high and low grade gliomas from the view point of nucleic acid metabolism.

Adult↗
PubMed1995

WS75624 A and B, new endothelin converting enzyme inhibitors isolated from Saccharothrix sp. No. 75624. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.

Novel endothelin converting enzyme (ECE) inhibitors, WS75624 A and B, have been isolated from the fermentation broth of Saccharothrix sp. No. 75624. These inhibitors were purified from an acetone extract of whole culture broth followed by HP-20 column chromatography, silica gel column chromatography and HPLC. WS75624 A and B showed highly potent ECE inhibitory activity, and both had IC50 values of 0.03 microgram/ml. WS75624 A and B also showed other metalloprotease (collagenase and neutral endopeptidase) inhibitory activity with IC50 values of 1 microgram/ml. Since large amount of WS75624 B was isolated, we tried in vivo evaluation using WS75624 B. WS75624 B inhibited big endothelin-induced pressor effect when administered to SD rat intravenously with big ET-1.

Animals↗
PubMed1995

Biological and pharmacological properties of highly selective new endothelin converting enzyme inhibitor WS79089B isolated from Streptosporangium roseum No. 79089.

WS79089B a highly specific endothelin converting enzyme (ECE) inhibitor has been isolated from the fermentation broth of Streptosporangium roseum No. 79089. WS79089B showed highly selective ECE inhibition activity with IC50 value of 0.14 microM and behaved as a competitive inhibitor of ECE, with Ki values of 8.9 x 10(-8) M. The sodium salt of WS79089B (FR901533) inhibited big endothelin-1 (big ET-1) induced pressor effect in a dose dependent manner when administered to male Sprague-Dawley rats intravenously dosed 2 minutes prior to big ET-1 challenge.

Actinomycetales↗
PubMed1994

WS79089A, B and C, new endothelin converting enzyme inhibitors isolated from Streptosporangium roseum. No. 79089. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.

WS79089A, B and C, which are novel endothelin converting enzyme (ECE) inhibitors have been isolated from the fermentation broth of Streptosporangium roseum No. 79089. These inhibitors were purified from an acetone extract of whole culture broth followed by Silicar CC-4 column chromatography and HPLC. WS79089A, B and C showed highly selective ECE inhibition activity with IC50 values of 0.73 microM 0.14 microM and 3.42 microM, respectively. On the basis of spectroscopic and chemical evidence, the tentative structures of WS79089A, B and C have been proposed, they have benzo[a]naphtacen chromophores.

Actinomycetales↗
PubMed1994

[Quadricuspid aortic valve: three case reports and review of the literature].

Three patients with grade 3 aortic regurgitation caused by rare congenital quadricuspid valve underwent aortic valve replacement. Patients were two females (51 and 45 years old) and a 51 year-old male. The first case showed 2 equal larger and 2 equal smaller valves. In the latter two cases, 4 equal sized cusps were noted. Fibrous trabeculations bridging the aortic wall and the commissures, giving an appearance of a hammock, were noted in the third case. Small fenestations were also noted in two cusps in this case. These findings may suggest dysplastic feature of the quadricuspid aortic valve. Hypertension seemed to have played an important role in the occurrence of regurgitation in their 4th or 5th decade of life. Their postoperative courses were uneventful.

Aortic Valve↗
PubMed1993

Brain tumor accumulation and plasma pharmacokinetic parameters of 2'-deoxy-5-18F-fluorouridine.

Using positron emission tomography and radio-high performance liquid chromatography, the accumulation of 2'-deoxy-5-18F-fluorouridine in the brain tumors and plasma pharmacokinetic parameters were investigated in 20 patients. High accumulation of the tracer in high grade gliomas and meningiomas and very rapid degradation of the tracer in the plasma were found. Very large variations were observed in both tumor accumulation and pharmacokinetic data. The tumor accumulation, however, did not correlate with any of the plasma pharmacokinetic parameters: area under the plasma concentration-time curve, mean residence time, total body clearance and steady-state volume of distribution. The results suggest that the accumulation of the tracer reflects the metabolic activity of the brain tumor tissues and that the effect of the rapid metabolic change in the tracer in the plasma on the tumor accumulation may be minor.

Adult↗
PubMed1992

A new angiogenesis inhibitor, FR-111142.

FR-111142 is a new angiogenesis inhibitor produced by a fungus Scolecobasidium arenarium F-2015. FR-111142 inhibited endothelial cell proliferation in vitro and angiogenesis in the growing chick chorioallantoic membrane model in vivo. Further, FR-111142 also suppressed the solid tumor growth in mice.

Allantois↗
PubMed1992

WF11605, an antagonist of leukotriene B4 produced by a fungus. I. Producing strain, fermentation, isolation and biological activity.

WF11605, a new antagonist of leukotriene B4 (LTB4) was isolated as a product of fungal strain F11605. The molecular formula of WF11605 was determined to be C38H60O11. WF11605 inhibited LTB4-induced chemotaxis of rabbit polymorphonuclear leukocytes (PMNLs) with an IC50 value of 1.7 x 10(-7) M and blocked 3H-LTB4 binding to PMNL membranes at 5.6 x 10(-6) M (IC50). WF11605 also inhibited LTB4-induced degranulation of rabbit PMNLs at 3.0 x 10(-6) M (IC50). However, WF11605 did not show any inhibitory effect on platelet activating factor (PAF)- and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-induced degranulation at concentrations up to 10(-4) M. These results suggest that WF11605 is a specific antagonist of LTB4.

Animals↗
PubMed1991

WF-2421, a new aldose reductase inhibitor produced from a fungus, Humicola grisea.

WF-2421 is a novel aldose reductase inhibitor produced by Humicola grisea. WF-2421 was purified from the culture filtrate by successive ion exchange chromatography and the chemical structure was assigned to be alpha-formamido-5'-(2-formamido-1-hydroxyethyl)- beta,2',6-trihydroxy-3-biphenylpropanoic acid (1) on the basis of spectroscopic evidence. The IC50 value of WF-2421 was 3 x 10(-8) M against partially purified aldose reductase of rabbit lens.

Aldehyde Reductase↗
PubMed1990

18F-fluoro-2'-deoxyuridine as a tracer of nucleic acid metabolism in brain tumors.

The value of 18F-fluoro-2'-deoxyuridine (18F-FUdR) as a tracer for nucleic acid metabolism was studied using an experimental rat brain-tumor model. The 18F activity in the tumor tissue 45 minutes after intravenous injection of 18F-FUdR was about 12 times higher than that in the contralateral cortex. Double-labeled autoradiography with 18F-FUdR and 14C-thymidine revealed similar brain-tumor images. In contrast, an autoradiographic comparison of 18F-FUdR with 14C-aminoisobutyric acid, which reveals the impairment of the blood-brain barrier, showed very different images. Also, the 18F radioactivity in the tumor tissue was at a constant level for 30 to 120 minutes, whereas a notable increase in 18F activity with time was observed in nucleotides and acid-insoluble fractions. These results suggest that the distribution pattern of 18F-FUdR closely correlates with the metabolism of nucleic acid and that this drug could be a useful tracer for positron emission tomography.

Animals↗