Increased expression of hemostasis markers in the coronary circulation in patients with coronary artery disease.
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Biomarkers↗
Biomedical subjects
Y Hojo
Publications and source records attributed to Y Hojo.
Interaction between human monocytes and vascular smooth muscle cells induces vascular endothelial growth factor expression.
The objective of this study was to investigate whether synthesis of vascular endothelial growth factor (VEGF), a major mitogen for vascular endothelial cells, was induced by a cell-to-cell interaction between monocytes and vascular smooth muscle cells (VSMCs). Human VSMCs and THP-1 cells (human monocytoid cell) were cocultured. VEGF levels in the coculture medium were determined by enzyme-linked immunosorbent assay. Northern blot analysis of VEGF mRNA was performed using a specific cDNA probe. Immunohistochemistry was performed to determine which types of cell produce VEGF. Adding THP-1 cells to VSMCs for 24 h increased VEGF levels of the culture media, 8- and 10-fold relative to those of THP-1 cells and VSMCs alone, respectively. Northern blot analysis showed that VEGF mRNA expression was induced in the cocultured cells and peaked after 12 h. Immunohistochemistry disclosed that both types of cell in the coculture produced VEGF. Separate coculture experiments revealed that both direct contact and a soluble factor(s) contributed to VEGF production. Neutralizing anti-interleukin (IL)-6 antibody inhibited VEGF production by the coculture of THP-1 cells and VSMCs. A cell-to-cell interaction between monocytes and VSMCs induced VEGF synthesis in both types of cell. An IL-6 mediated mechanism is at least partially involved in VEGF production by the cocultures. Local VEGF production induced by a monocyte-VSMC interaction may play an important role in atherosclerosis and vascular remodeling.
Blotting, Northern↗
Interaction between monocytes and vascular smooth muscle cells induces expression of hepatocyte growth factor.
OBJECTIVE: To investigate the expression of hepatocyte growth factor (HGF)--a multifunctional factor implicated in tissue regeneration, wound healing and angiogenesis--that is induced by cell-to-cell interactions between monocytes and vascular smooth muscle cells (VSMCs), using coculture of human VSMCs and cells of the human monocytoid cell line, THP-1. METHODS: We collected supernatant from the coculture medium and measured HGF concentrations with an enzyme-linked immunosorbent assay. Northern blot analysis of HGF mRNA was performed using a specific cDNA. To explore which types of cells produce HGF, we performed immunohistochemistry. RESULTS: Coculture of VSMCs with THP-1 cells for 24 h caused a fivefold increase in HGF concentrations over that in control VSMC culture. Northern blot analysis showed an induction of HGF mRNA in the coculture with a peak at 3 h. Separated cocultures demonstrated that both direct contact and soluble factors contribute to the production of HGF. Immunohistochemistry demonstrated that both types of cells in the coculture produce HGF. Neutralizing antibodies against tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 inhibited the HGF production in THP-1 cells and VSMCs that was induced by the coculture conditioned medium. The protein kinase C inhibitors H-7, calphostin C and K252b, and the tyrosine kinase inhibitor, genistein, significantly inhibited the production of HGF in the coculture. CONCLUSIONS: Cell-to-cell interactions between monocytes and VSMCs induced HGF synthesis in both types of cells, suggesting that local HGF production induced by this cell-to-cell interaction has an important role in the pathogenesis of hypertension, atherosclerosis or vascular remodelling.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Amlodipine inhibits expression of matrix metalloproteinase-1 and its inhibitor in human vascular endothelial cells.
Matrix metalloproteinase-1 (MMP-1) may play an important role in the pathogenesis of atherosclerosis and atherosclerotic plaque rupture. We investigated the effect of the calcium channel blockers amlodipine and nifedipine on the expression of MMP-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in endothelial cells (ECs). MMP-1 and TIMP-1 levels in conditioned media of human vascular ECs were measured by enzyme-linked immunosorbent assay. Collagenolytic activity was determined by fluorescence-labeled collagen digestion. The addition of interleukin-1beta (IL-1beta) increased MMP-1 levels in the culture media of ECs. Amlodipine, but not nifedipine, significantly decreased MMP-1 levels in IL-1beta-stimulated ECs. TIMP-1 levels also were significantly increased by IL-1beta, and its expression was slightly decreased by amlodipine, not by nifedipine. Amlodipine significantly inhibited collagenolytic activity in the culture media of IL-1beta-stimulated ECs, whereas nifedipine showed no significant effect on the activity. Our findings revealed that amlodipine, but not nifedipine, inhibits IL-1beta-induced MMP-1 expression in human ECs.
Amlodipine↗
Interaction between monocytes and vascular smooth muscle cells enhances matrix metalloproteinase-1 production.
Matrix metalloproteinase-1 (MMP-1) plays an important role in atherosclerotic plaque rupture. The purpose of this study was to investigate the expression of MMP-1 by cell-to-cell interactions between monocytes and vascular smooth muscle cells (VSMCs). Human VSMCs and THP-1 cells (human monocytoid cells) were cocultured. MMP-1 levels were measured by enzyme-linked immunosorbent assay. Collagenolytic activity was determined by fluorescent labeled-collagen digestion. Immunohistochemistry was performed to determine which types of cells produce MMP-1. Adding THP-1 cells to VSMCs markedly increased the MMP-1 levels and activity of the culture media. MMP-1 levels were maximal when the cellular ratio of THP-1 cells/VSMCs was 1.0. Immunohistochemistry revealed that both types of cells in the coculture produced MMP-1. Separated coculture experiments showed that both direct contact and a soluble factor(s) contributed to MMP-1 production. Neutralizing anti-interleukin (IL)-6 and tumor necrosis factor-alpha antibodies inhibited coculture conditioned medium-induced MMP-1 production by VSMCs and THP-1 cells. Protein kinase C inhibitors, tyrosine kinase inhibitors, and a mitogen-activated protein kinase inhibitor significantly inhibited MMP-1 production by cocultures. Direct cell-to-cell interaction between THP-1 cells and VSMCs enhanced MMP-1 synthesis in both types of cells. Increased local MMP-1 production and activity induced by monocyte-VSMC interaction play an important pathogenic role in atherosclerotic plaque rupture.
Cell Adhesion↗
Production of hepatocyte growth factor during acute myocardial infarction.
OBJECTIVE: To investigate the clinical significance of circulating hepatocyte growth factor (HGF) and the role of peripheral blood mononuclear cells (monocytes), which are a possible source of HGF, in patients with acute myocardial infarction. DESIGN AND PATIENTS: 37 patients with acute myocardial infarction and 13 normal control subjects were recruited. Peripheral venous blood samples were drawn from the infarct patients 1, 7, 14, and 21 days after onset. Monocytes were isolated from peripheral blood at those times. HGF concentrations in serum and in a culture medium of monocytes after incubation for 24 hours (monocyte HGF levels) were measured by enzyme linked immunosorbent assay. RESULTS: Serum HGF and monocyte HGF values within seven days after onset of myocardial infarction were significantly higher than those of control subjects and decreased by day 14. There were significant positive correlations between serum HGF and monocyte HGF levels on day 7; between maximum plasma creatine phosphokinase levels and serum HGF levels on day 1; between maximum plasma C reactive protein and serum HGF levels; and between maximum C reactive protein and monocyte HGF levels. Monocyte HGF levels were raised in the patients with progression of ventricular enlargement in the course of acute myocardial infarction. CONCLUSIONS: Early serum HGF concentrations reflect the extent of myocardial damage in acute myocardial infarction patients. Inflammation after acute myocardial infarction is supposed to be involved in enhanced HGF production. Monocytes may play an important role in ventricular remodelling after acute myocardial infarction by releasing the cardiovascular protective mitogen HGF.
Adult↗
Inhibition of angiotensin converting enzyme cannot prevent increases in angiotensin II production in coronary circulation.
OBJECTIVE: To determine whether inhibition of angiotensin converting enzyme (ACE) can prevent angiotensin II production in the coronary circulation induced by percutaneous transluminal coronary angioplasty (PTCA) in patients with myocardial ischaemia. DESIGN, PATIENTS: 41 patients who underwent elective PTCA and six control subjects who received diagnostic coronary angiography were studied. Patients were divided into two groups according to the chronic administration of ACE inhibitors (group A, 15 patients treated with ACE inhibitors; group B, 26 patients without ACE inhibitors). Blood samples were drawn through catheters placed in the aorta and coronary sinus before and 24 hours after PTCA. RESULTS: Mean levels of ACE activity in the aorta were significantly lower in patients in group A than in group B. However, mean angiotensin II concentrations in the aorta were not significantly different between the two groups. Differences in basal angiotensin II concentrations between the coronary sinus and aorta, which reflected basal angiotensin II production in the coronary circulation, were not significant among group A, group B, and control subjects. The production of angiotensin II in the coronary circulation was significantly increased 24 hours after PTCA in both group A and group B to the same extent. No significant changes were observed in control subjects 24 hours after diagnostic coronary angiography. CONCLUSIONS: This study revealed that inhibition of ACE activity by ACE inhibitors could not prevent increases in angiotensin II production in the coronary circulation induced by PTCA.
Adult↗
Interleukin 6 expression in coronary circulation after coronary angioplasty as a risk factor for restenosis.
OBJECTIVE: To investigate changes in cytokine expression in the coronary circulation induced by percutaneous transluminal coronary angioplasty (PTCA). METHODS: The study involved 32 patients with ischaemic heart disease who underwent elective PTCA for isolated stenotic lesions of the left coronary artery. Ten patients had plain old balloon angioplasty, 10 had percutaneous transluminal rotational atherectomy, and 12 had stent implantation. Blood samples were drawn from the coronary sinus before and immediately after PTCA. Plasma concentrations of interleukin 6 (IL-6), platelet derived growth factor (PDGF), monocyte chemoattractant protein 1 (MCP-1), and macrophage coronary stimulating factor (M-CSF) were measured. The patients were scheduled for follow up angiography six months after PTCA. Late loss index was calculated using quantitative coronary angiography. RESULTS: IL-6 concentrations in coronary sinus blood increased immediately after PTCA (p < 0.001), but there was no change in PDGF, MCP-1, or M-CSF. There was a positive correlation between changes in IL-6 concentrations immediately after PTCA and late loss index six months after PTCA (r = 0.73, p < 0.001). IL-6 concentrations in coronary sinus blood were higher in patients with late restenosis than in those without restenosis (p < 0.001). CONCLUSIONS: PTCA induces IL-6 production in the coronary circulation. This may induce subsequent inflammatory responses in injured vessels and play an important role in late restenosis after PTCA.
Adult↗
Decreased adrenomedullin production in the coronary circulation of patients with coronary artery disease.
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Adrenomedullin↗
[Hepatotoxicity induction in mice after acute DL-lactic acid intake].
DL-Lactic acid and its salts are added to food as acidulants, pH control agents, leavening agents, nutrient supplements and seasonings. However, the basic data concerning the safety and toxicity of these compounds are insufficient. In this article, we examined induction of hepatotoxicity and nephrotoxicity in mice after acute intake of DL-lactic acid. Body weight change, serum glutamic pyruvic transaminase (SGPT) activity, serum urea nitrogen (SUN) concentration, liver and kidney weights, and renal lipid peroxide level could not be affected significantly in mice at 4 h after intraperitoneal administration of DL-lactic acid at 1.2 mmol/kg, indicating no induction of toxicity in the liver and kidney. In contrast, at 20 h after the treatment, SGPT activity, liver weight and lipid peroxide level were enhanced significantly, suggesting induction of hepatotoxicity. However, SUN concentration, kidney weight and lipid peroxide level could not be affected significantly at 20 h after the treatment, indicating no induction of nephrotoxicity.
Administration, Oral↗
[In vivo toxicity, lipid peroxide lowering, and glutathione, ascorbic acid and copper elevation induced in mouse liver by low dose of oxine-copper, a fungicide].
While oxine-copper (OxCu) is generally used as an agricultural fungicide and induces a harmful effect on ecosystems, little information is available regarding a toxic effect of OxCu on mammals. In this article, we examined in vivo induction of toxicity and change of levels of glutathione and ascorbic acid, major biological antioxidants, lipid peroxide and copper (Cu) in liver and kidney 4 h and 24 h after intraperitoneal administration of OxCu at a low dose (0.05 mmol/kg) to mice. Increased hepatic ascorbic acid and Cu levels were found at 4 h after the treatment. In addition, body weight change was lowered and serum glutamic pyruvic transaminase activity was elevated significantly compared to control at 24 h after the treatment, suggesting induction of systemic and hepatic toxicity respectively. These were accompanied by lowered lipid peroxide level and enhanced glutathione, ascorbic acid and Cu levels in the mouse liver. On the other hand, OxCu induced no elevation in serum urea nitrogen concentration 4 h and 24 h after the treatment, suggesting no induction of nephrotoxicity, accompanied by no change in renal lipid peroxide, glutathione, ascorbic acid and Cu levels. These results suggest that hepatic Cu elevation may induce hepatotoxicity and no renal Cu elevation may lead to no induction of nephrotoxicity after the treatment with OxCu.
Animals↗
[In vivo toxicity, and glutathione, ascorbic acid and copper level changes induced in mouse liver and kidney by copper(II) gluconate, a nutrient supplement].
While copper(II) gluconate (CuGL) is generally used as a nutrient supplement for infant foods and as an oral deodorant, little information is available regarding a toxic effect of CuGL on mammals. In this article, we examined in vivo induction of toxicity and change of level of glutathione and ascorbic acid, major biological antioxidants, lipid peroxide and copper (Cu) in liver and kidney 4 h after single intraperitoneal administration of CuGL at 0.05 and 0.10 mmol/kg to mice. Serum glutamic pyruvic transaminase (SGPT) activity, an indicator of hepatotoxicity, significantly increased compared to control in proportion to doses of CuGL. Hepatic level of glutathione measured as nonprotein sulfhydryl was not proportional to CuGL doses, but enhanced after dosing of 0.05 mmol/kg and lowered by 0.10 mmol/kg. Like SGPT activity, serum urea nitrogen (SUN) concentration, an indicator of nephrotoxicity, significantly increased in proportion to doses of CuGL. Renal glutathione level was not different from control after dosing of 0.05 mmol/kg and lowered by 0.10 mmol/kg. In both organs, relative organ weight and lipid peroxide level were not affected by the treatment with CuGL; ascorbic acid level was elevated after dosing of 0.05 mmol/kg and was not different from control after treatment with 0.10 mmol/kg; like SGPT activity and SUN concentration, Cu level significantly increased in proportion to doses of CuGL. These results suggest that in the liver and kidney after the treatment with CuGL Cu accumulated may induce toxicity, leading to level changes of glutathione and ascorbic acid and to no induction of oxidative damage.
Animals↗
Direct evidence for in vivo hydroxyl radical generation in blood of mice after acute chromium(VI) intake: electron spin resonance spin-trapping investigation.
Although it is assumed from in vitro experiments that the hydroxyl radical (*OH) may be responsible for chromium(VI) toxicity/carcinogenicity, no electron spin resonance (ESR) evidence for the generation of *OH in vivo has been reported. In this study, we have employed an ESR spin-trapping technique with 5,5-dimethylpyrroline-N-oxide (DMPO), a selective *OH trap, to detect *OH in blood. The ESR spectrum of spin adduct observed in the blood of mice given 4.8 mmol Cr(VI)/kg body weight exhibited the 1:2:2:1 intensity pattern of a quartet with a hyperfine coupling constant A(N) = A(H) = 14.81 G and g-value = 2.0067. The concentration of the spin adduct detected in the blood was 7.37 microM. The adduct production was inhibited by the addition of specific *OH scavengers such as sodium benzoate and methional to the blood. The results indicate that the spin adduct is nitroxide produced by the reaction of *OH with DMPO. This is the first report of ESR evidence for the in vivo generation of *OH in mammals by Cr(VI).
Aldehydes↗
In vivo singlet-oxygen generation in blood of chromium(VI)-treated mice: an electron spin resonance spin-trapping study.
Although it is assumed from in vitro experiments that the generation of reactive oxygen species such as the singlet oxygen (1O2), the hydroxyl radical, and the superoxide anion are responsible for chromium(VI) toxicity/carcinogenicity, no electron spin resonance (ESR) evidence for the generation of 1O2 in vivo has been reported. In this study, we have employed an ESR spin-trapping technique with 2,2,6,6-tetramethyl-4-piperidone (TMPD), a specific 1O2 trap, to detect 1O2 in blood. The ESR spectrum of the spin adduct observed in the blood of mice given 4.8 mmol Cr(VI)/kg body weight exhibited the 1:1:1 intensity pattern of three lines with a hyperfine coupling constant A(N) = 16.08 G and a g-value = 2.0066. The concentration of spin adduct detected in the blood was 1.46 microM (0.1% of total Cr concentration). The adduct production was inhibited by the addition of specific 1O2 scavengers such as 1,4-diazabicyclo[2.2.2]octane and sodium azide to the blood. The results indicate that the spin adduct is nitroxide produced by the reaction of 1O2 with TMPD. This is the first report of ESR evidence for the in vivo generation of 1O2 in mammals by Cr(VI).
Animals↗
Enhanced inflammatory response to coronary angioplasty in patients with severe unstable angina.
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Acute-Phase Reaction↗
Significant differences in the frequency of transcriptional units, types and numbers of repetitive elements, GC content, and the number of CpG islands between a 1010-kb G-band genomic segment on chromosome 9q31.3 and a 1200-kb R-band genomic segment on chromosome 3p21.3.
We determined the nucleotide sequence of the entire 1,010,525-bp insert contained in CEPH YAC clone 867e8. This human genomic segment was derived from chromosome 9q31.3 and corresponds to a G-band region. We compared this segment, in terms of structure, with a previously characterized 1,201,033-bp sequence in CEPH YAC936c1 that had come from a portion of human chromosome 3p21.3 corresponding to an R-band region. The two segments were significantly different with respect to the frequency of transcriptional units, the types and numbers of repetitive elements present, their GC content, and the number of CpG islands. Alu elements, GC content, and CpG islands all showed positive correlations with the abundance of exons, but the distribution of LINE1s did not. These observations might reflect an influence of the first three of these features on the functions or expression of genes in the respective regions. In addition to a novel gene (F36) lying at the centromeric end of the 9q segment, we found a cluster of placenta-specific genes within a small section (about 400 kb) on the telomeric side of YAC867e8. This cluster consisted of four apparently unrelated ESTs and two genes, pregnancy-associated plasma protein-A (PAPP-A) and a novel gene (tentatively named EST-YD1). Our characterization of the two chromosomal regions provided evidence that genes are not evenly distributed throughout the human genome, and that gene richness is correlated with the GC content and with the frequency of either Alu elements or CpG islands.
Alu Elements↗
Angiotensin-converting enzyme inhibition as antiatherosclerotic therapy: no answer yet.
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Angiotensin I↗
Characterization of a 1200-kb genomic segment of chromosome 3p22-p21.3.
We previously determined the nucleotide sequence and characterized the 685-kb proximal half of CEPH YAC936c1, which corresponds to a portion of human chromosome 3p21.3. In the study reported here, we characterized the remaining 515-kb of this YAC clone corresponding to the telomeric half of its human insert. The newly sequenced region contained a total of ten genes including six reported previously: phospholipase C delta 1 (PLCD1), human activin receptor type IIB (hActR-IIB), organic cation transporter-like 1 (OCTL1), organic cation transporter-like 2 (OCTL2), oxidative stress response 1 (OSR1), and human xylulokinase-like protein (XYLB). The remaining four genes present in the telomeric region included two known genes, MyD88 and ACAA, and two novel genes. One (designated ENGL) of the novel sequences was found to encode an amino-acid sequence homologous to the family of DNA/RNA endonucleases, especially endonuclease G. The other gene F56 revealed no significant homology to any known genes. These results disclosed complete physical and transcriptional maps of the 1200-kb region of 3p present in YAC 936c1.
Amino Acid Sequence↗