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Biomedical subjects

J Ogata

Publications and source records attributed to J Ogata.

At least 19 recordsLinked to original sources
PubMed2000

Deletion allele of angiotensin-converting enzyme gene increases risk of essential hypertension in Japanese men : the Suita Study.

BACKGROUND: The Framingham Study recently revealed that the homozygous deletion polymorphism of the angiotensin-converting enzyme gene (ACE DD) is associated with increased risk for essential hypertension in a male-specific manner. However, this association has not been confirmed in races other than whites. METHODS AND RESULTS: Using a large number of Japanese subjects (n=5014) that were randomly selected from the general population (the Suita Study), we examined the association between ACE DD and hypertension. The frequency of DD (17.1%) in hypertensive men was significantly higher (P<0.0015) than that (11.8%) in other mildly hypertensive or normotensive men, and the estimated odds prevalence for hypertension (DD vs II) was 1.75 (95% CI 1.21 to 2.53). In contrast, no significant association was confirmed in women (OR 1.17, 95% CI 0.79 to 1.72). CONCLUSIONS: Despite the lower frequency of the DD genotype in Japanese than in whites, the ACE gene polymorphism was associated with increased risk for hypertension, suggesting that this polymorphism is a mild but certain genetic risk factor for essential hypertension in men.

Age Factors↗
PubMed2000

Linkage between alpha(1) adrenergic receptor and the Jak/STAT signaling pathway in vascular smooth muscle cells.

The Jak/STAT pathway is activated following stimulation of the type I angiotensin II receptor. To examine whether this pathway is shared among other G-protein-coupled receptors, we studied the linkage between the alpha(1) adrenergic receptor and this pathway. The alpha(1) agonist phenylephrine induced tyrosine phosphorylation of Jak2, Tyk2, and STAT1 in vascular smooth muscle cells. The phosphorylation of Jak2 was prevented by the alpha(1) receptor antagonists prazosin and chloroethylclonidine, but not by WB4101, and that of STAT1 was inhibited by prazosin and the Jak2 inhibitor AG490. After stimulation with phenylephrine, Jak2 and STAT1 were found to associate with alpha(1B) receptor. Phenylephrine stimulated the DNA binding activity of STAT1. Protein synthesis promoted by phenylephrine was inhibited by prazosin, AG490, and the introduction of a decoy oligonucleotide for STAT1. These results suggested that alpha(1) receptor is linked to the Jak/STAT pathway and that this pathway mediates alpha(1) agonist-induced smooth muscle hypertrophy.

Adrenergic alpha-Agonists↗
PubMed2000

[Congenital thrombophilia caused by protein C deficiency].

To clarify the prevalence of protein C deficiency in patients with cardiovascular problems, we identified 54 patients with protein C deficiency by screening approximately 26,800 patients. The observed prevalence of protein C deficiency was 1 in 500. From the results of genetic analysis of 67 Japanese families with protein C deficiency, the recurrent defects of Phe139Val, Arg169Trp, Val297Met, Met364Ile substitutions and a G8857 deletion were accounting 49% of Japanese families with protein C deficiency. The defects including Phe139Val and Met364Ile substitutions and a G8857 deletion were only found in Japanese subjects and seemed to be a founder effect. Protein C deficiency is associated with a predisposition to venous thrombosis. It is not clear whether the deficiency is involved in arterial occlusion. We identified 34 patients with protein C deficiency manifested 45 episodes of arterial occlusive disease. We compared the onset age of arterial occlusive disease between patients with protein C deficiency and a group of patients with normal protein C levels. We found the early onset of acute myocardial infarction and atherothrombotic cerebral infarction in patients with protein C deficiency. Thus, our study suggests that congenital protein C deficiency contributes to earlier onset of arterial occlusive diseases in Japanese subjects.

Arterial Occlusive Diseases↗
PubMed1999

Human prostacyclin synthase gene and hypertension : the Suita Study.

BACKGROUND: Prostacyclin (prostaglandin I(2)) is a strong vasodilator that inhibits the growth of vascular smooth muscle cells and is also the most potent endogenous inhibitor of platelet aggregation. Therefore, it has been considered to play an important roles in cardiovascular disease. On the basis of the hypothesis that variations of the prostacyclin synthase gene may also play an important role in human cardiovascular disease, we performed a screening for variations in the human prostacyclin synthase gene. METHODS AND RESULTS: We have detected a repeat polymorphism in the promoter region of the human prostacyclin synthase gene. The number of 9-bp (CCGCCAGCC) repeats in the promoter region, which encodes a tandem repeat of Sp1 transcriptional binding sites, varied between 3 and 7 in Japanese subjects. Luciferase reporter analysis indicated that the alleles of 3 and 4 repeats (R3 and R4, respectively) had less promoter activity in cultured human umbilical vein endothelial cells. We then investigated the possible association of this repeat polymorphism with blood pressure in a large population-based sample (the Suita Study), which consisted of 4971 Japanese participants. Multivariate models indicated that participants with the R3R3, R3R4, or R4R4 genotype (SS genotype, n=80) had significantly higher systolic pressure (P=0.0133) and pulse pressure (P=0.0005). The odds ratio of hypertension (140/90 mm Hg) for the SS genotype was 1.942 (95% confidence interval 3.20 to 1.19, P=0.0084). CONCLUSIONS: Repeat polymorphism of the human prostacyclin synthase gene seems to be a risk factor for higher pulse pressure and is consequently a risk factor for systolic hypertension in the Japanese population.

Adult↗
PubMed1999

Association of smooth muscle cell phenotypic modulation with extracellular matrix alterations during neointima formation in rabbit vein grafts.

PURPOSE: To clarify the mechanisms of structural changes underlying vein graft stenosis that limits efficacy of bypass grafting operation, we examined the accumulation and distribution of various extracellular matrix (ECM) components during neointima formation in rabbit vein grafts and analyzed their correlation with proliferation and phenotypic modulation of smooth muscle cells (SMCs). METHODS AND RESULTS: An autologous external jugular vein graft was transplanted into the carotid artery in 25 rabbits. After the restoration of blood flow, the graft was markedly dilated. Medial SMCs in the graft appeared to be injured, and they began to proliferate at day 4 and subsequently migrated and formed the neointima at day 7. The neointima observed at days 7 and 14 contained ECM components, including type I collagen, heparan sulfate, and chondroitin sulfate, and the intimal SMCs were phenotypically modulated from the differentiated-type (SM2-positive and SM embryonic-negative) to the dedifferentiated-type (SM2-negative and SM embryonic-positive) as determined with immunostainings for myosin heavy chain isoforms. The intimal SMC proliferation was maximal at 2 weeks and then decreased rapidly. However, the neointima continued to thicken thereafter throughout the 6-month period of the experiment, and ECM accumulation, such as type I collagen and decorin, a small dermatan sulfate proteoglycan, was a prominent feature observed in the hypocellular region of the deep intima from 2 months after the transplantation. The phenotype of the intimal SMCs gradually returned to the differentiated-type from the deep intima after 2 months, but a small number of the intimal SMCs remained in the dedifferentiated phenotype even at 6 months after the operation. CONCLUSION: The neointima in the vein graft was formed initially by means of migration and proliferation of the phenotypically modulated, dedifferentiated-type SMCs and continued to thicken by means of sustained ECM accumulation, including type I collagen and decorin, in association with the prolonged presence of the dedifferentiated-type SMCs. These chronologic features in cell kinetics and ECM accumulation may contribute to the frequent occurrence of graft wall thickening that occurs in the vein grafts.

Animals↗
PubMed1999

Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro.

UNLABELLED: The production of proinflammatory cytokines, such as tumor necrosis factor (TNF) a, interleukin (IL)-6, and IL-8, increases in patients with sepsis; marked production causes organ failure and septic shock. We previously reported that ketamine suppressed lipopolysaccharide (LPS)-induced TNF-alpha production in mice. However, there are no reports on the effect of ketamine on cytokine production in human whole blood. Therefore, in this study, we investigated the efficacy of ketamine on LPS-induced TNF-alpha, IL-6, and IL-8 production and recombinant human (rh) TNF-a-induced IL-6 and IL-8 production in human whole blood. After adding different doses of ketamine to whole blood, the blood was stimulated with LPS or rhTNF. After incubation, the plasma TNF-alpha activity and IL-6 and IL-8 concentrations were measured using the L929 cell cytotoxic assay or an enzyme-linked immunoassay. Ketamine significantly suppressed LPS-induced TNF-alpha production at concentrations >20 microg/mL. At concentrations >100 microg/mL, ketamine also significantly suppressed both LPS-induced and rhTNF-induced IL-6 and IL-8 production. In this study, we demonstrated that ketamine directly inhibits the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-8 in human whole blood. IMPLICATIONS: We found that ketamine suppressed lipopolysaccharide-induced tumor necrosis factor alpha, interleukin (IL)-6, and IL-8 production and recombinant human tumor necrosis factor-induced IL-6 and IL-8 production in human whole blood. Ketamine directly suppresses proinflammatory cytokine production.

Anesthetics, Dissociative↗
PubMed1998

Oscillating thromboemboli within the extracranial internal carotid artery demonstrated by ultrasonography in patients with acute cardioembolic stroke.

We detected oscillating thromboemboli at the extracranial internal carotid artery (ICA) by duplex carotid ultrasonography in patients with acute cardioembolic stroke. Using B-mode ultrasonography, we evaluated the extracranial ICA in 11 patients with acute cardioembolic ICA occlusion. A homogeneous, elastic, oscillating intraluminal mass echo originating in the extracranial ICA extended distally in 5 (46%) of these patients. The echoes moved quickly and distally during the systolic phase of the cardiac cycle and returned slowly to the original position during the diastolic phase. We performed a postmortem study 24 days after stroke onset in 1 patient with an oscillating intraluminal mass echo that had been demonstrated by duplex ultrasonography. The ICA lumen was obstructed with a fresh string-like thrombus. The findings of oscillating intraluminal mass echo may help establish a diagnosis of acute embolic ICA occlusion.

Acute Disease↗
PubMed1997

Induction of the cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1) by nitric oxide-generating vasodilator in vascular smooth muscle cells.

Nitric oxide-generating vasodilators inhibit vascular smooth muscle cell proliferation. To elucidate the mechanism underlying this process, we investigated the effect of S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide-releasing agent, on the smooth muscle cell cycle. When G0 cells were stimulated with fetal bovine serum and basic fibroblast growth factor, DNA synthesis assessed by [3H]thymidine incorporation started about 15 h later. SNAP dose-dependently inhibited this incorporation, and this effect was maximal at 100 microM. This inhibition was attenuated when SNAP was added after 9-12 h. SNAP inhibited the activity of cyclin-dependent kinase 2 (Cdk2) and phosphorylation of the retinoblastoma protein, both of which usually increased from about 9 h, whereas it did not inhibit the activities of cyclin D-associated kinase(s), Cdk4, and Cdk6, which normally increased from 0-3 h. Although SNAP reduced the mRNA levels of cyclins E and A, it neither reduced their protein levels nor impaired their association with Cdk2. SNAP did not reduce the mRNA levels of cyclins G, C, and D1, Cdk2, Cdk4, and Cdk5, which were normally elevated from 0-3 h. The mRNA and protein levels of the Cdk inhibitor p21 were high in the early G1 phase, peaking at 3 h and then rapidly decreasing after 6 h. In the presence of SNAP, however, p21 expression was enhanced, and moreover, the later decrease disappeared. SNAP also increased the amount of Cdk2-associated p21. These results suggested that nitric oxide inhibits the G1/S transition by inhibiting Cdk2-mediated phosphorylation of the retinoblastoma protein and that p21 induction is involved in the Cdk2 inhibition.

Animals↗
PubMed1997

Basal forebrain and cerebral cortical muscarinic receptors mediate increase in cortical blood flow provoked by periaqueductal gray matter.

The midbrain periaqueductal gray matter has been identified as a reflex centre located uppermost in the central organization of diverse defensive reactions. We recently found that when activated, the caudal third of the lateral periaqueductal gray was also capable of provoking a marked increase in cortical blood flow. The response may be the combined outcome of a flow increase of nitrergic origin and that coupled to a possible concomitant cortical activation. In the present study, we attempted to clarify the neural substrates for mediation of the increase in flow (observed by laser-Doppler flowmetry), in 49 anaesthetized, artificially ventilated, and cervically cordotomized rats. The flow increase provoked by stimulation of the particular subdivision of the periaqueductal gray with N-methyl-D-aspartate (1 mM, 100 nl) was unaffected by i.v. pentolinium tartrate (10 mg/kg), suggesting little contribution by the cerebrovasodilator parasympathetic nervous system to the response. The response was abolished by i.v. or topical cortical administration of scopolamine hydrobromide (3.16 mg/kg or 1.0 mM, respectively). Placement of bilateral lesions in the basal forebrain with alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (15 mM) impaired the cortical choline acetyltransferase activity and attenuated the flow response. Overall, we suggest that the cholinergic corticopetal neurons of the nucleus basalis of Meynert and cortical muscarinic receptors may form a principal efferent arm of a central circuitry emanating from the subdivision of the periaqueductal gray, in the mediation of the increase in cortical blood flow and possible cortical activation.

Animals↗
PubMed1997

Role of platelet-activating factor in two-kidney, one-clip hypertension.

BACKGROUND: Platelet-activating factor (PAF) is a bioactive phospholipid which is a potent hypotensive agent. To investigate the role of PAF in renovascular hypertension, we determined the PAF concentration and its production level assessed by the activity of cholinephosphotransferase (CPT) in renal tissue and examined the effect of a PAF antagonist on the mean arterial pressure (MAP) in control and two-kidney with one clipped (2K1C) hypertensive rats. MATERIALS AND METHODS: The concentration of PAF and CPT in the renal medulla and cortex were determined by radioassay. Also, the effect of a PAF antagonist, CV-6209, on MAP was also examined in both 2K1C hypertensive and normal control rats. RESULTS: The PAF concentration and CPT activity were significantly higher in the medulla than in the cortex in both 2K1C hypertensive and normal control rats, and both values in the medulla were also significantly higher in the clipped kidney than in the contralateral unclipped kidney or in control rat kidneys. We also observed a significant negative correlation between the PAF concentration in the medulla, and the medulla weight in the clipped kidney of 2K1C hypertensive rats. Infusion of the PAF antagonist, CV-6209, did not affect MAP in 2K1C hypertensive rats, but was significantly increased (P < 0.05) in control rats. CONCLUSIONS: These findings suggest that PAF, whose production is induced by renal ischemia due to renal artery stenosis, plays an important role in the renomedullary vasodepressor system, but the effect of PAF as a vasodilator in the peripheral vessels is limited in 2K1C hypertension.

Animals↗
PubMed1996

Phorbol ester inhibits the phosphorylation of the retinoblastoma protein without suppressing cyclin D-associated kinase in vascular smooth muscle cells.

To elucidate the role of protein kinase C in vascular smooth muscle cell proliferation, we examined the effects of phorbol 12-myristate 13-acetate (PMA) on G1 events in human arterial cells. About 15 h after G0 cells were stimulated with fetal bovine serum and basic fibroblast growth factor, [3H]thymidine incorporation started. PMA (10 nM) inhibited the incorporation over 90% when added earlier than 3 h after stimulation, but had no effect when added 12 h or later. PMA inhibited the phosphorylation of the retinoblastoma protein (pRb), which normally began at about 9 h. PMA did not inhibit the gene expression of Cdk2, Cdk3, Cdk4, Cdk5, and cyclins G, C, and D, all of which began at 0-3 h. However, PMA reduced the expression of cyclins E and A, which usually began at 3-9 h and about 15 h, respectively. PMA inhibited the histone H1 kinase activity of Cdk2, which increased from about 9 h, whereas PMA did not inhibit the pRb kinase activities of cyclin D-associated kinase(s) and Cdk4, detectable from 0-3 h. These results suggested that the PMA-induced inhibition of pRb phosphorylation is not mediated by suppressing cyclin D-associated kinase(s) including Cdk4, but involves the suppression of Cdk2 activity that results from the reduced expression of cyclins E and A.

Cell Cycle↗
PubMed1996

The competitive NMDA antagonist, CGS-19755, improves postischemic hypoperfusion in selectively vulnerable regions in gerbils.

We attempted to clarify the effects of an NMDA antagonist on postischemic hypoperfusion in gerbils with 10 min forebrain ischemia and to relate it to postischemic metabolic recovery. We administered 10 mg/kg of CGS-19755, a competitive NMDA antagonist, or the same volume of saline intraperitoneally 30 min before the vascular occlusion. In 26 gerbils, we measured local cerebral blood flow (LCBF) 60 min after the reperfusion using [14C]iodoantipyrine autoradiography. In 20 gerbils, the effects on metabolic recovery were determined by serial measurements of intracellular pH, adenosine triphosphate (ATP) and the ratio between phosphocreatine and inorganic phosphate (PCr/Pi) until 60 min after reperfusion using 31P-magnetic resonance spectroscopy. In another group of 24 gerbils, we determined histopathological damage 24 h after the ischemia. The LCBF autoradiograms in the control group consistently demonstrated a typical postischemic hypoperfusion, i.e. homogeneous 50-75% reduction of blood flow in all forebrain structures. In contrast, CGS-19755 pretreatment animals showed highly heterogeneous LCBF declines, and significantly higher LCBF values were observed in the frontoparietal cortex and thalamus both of which were the most vulnerable area in this model. No significant LCBF change was observed in sham operated animals with or without CGS-19755 pretreatment. The postischemic recovery of PCr/Pi in gerbils pretreated with CGS-19755 was significantly better than that in the control animals. No significant differences in the recovery of ATP and intracellular pH were observed. The histological damage in the CGS-19755-treated group was less extensive than those in the saline-treated group. CGS-19755 pretreatment improved postischemic hypoperfusion and PCr/Pi recovery in the 10-min forebrain ischemia model in gerbils. The improvement of postischemic hypoperfusion in selectively vulnerable regions suggests that the activation of NMDA receptors may be related to the mechanism of developing postischemic hypoperfusion.

Animals↗
PubMed1996

Monocyte-derived macrophages prime peripheral T cells to undergo apoptosis by cell-cell contact via ICAM-1/LFA-1-dependent mechanism.

We designed the present study to clarify the mechanism of superantigen-induced apoptosis of human mature T cells and to elucidate the pivotal roles of monocyte-derived macrophages in induction of T cell apoptosis. Exposure of unfractionated human peripheral blood mononuclear cells to SEA, SEB or PHA elicited apoptosis in T cells after 5-day culture. In purified T cell preparations, SEB was unable to induce apoptosis, but was inductive when the purified T cells were cocultured with monocyte-derived macrophages adhering to plastic culture dishes. Placing the T cells in the insert wells which physically separated them from the adhering macrophages resulted in a complete loss of SEB-induced apoptosis. The addition of blocking antibodies against LFA-1, ICAM-1 and CD2 to the cocultures significantly inhibited the SEB-induced T cell apoptosis. We concluded therefore that direct contact of macrophages with T cells is critical in SEB-induced T cell apoptosis, and that adhesion molecules such as LFA-1/ICAM-1 and CD2 may be involved in the mechanism of this effect.

Apoptosis↗
PubMed1996

Abnormal expression of sphingomyelin acylase in atopic dermatitis: an etiologic factor for ceramide deficiency?

Previously, we demonstrated that there is a marked reduction in the amount of ceramide in the stratum corneum of both lesional and nonlesional forearms in atopic dermatitis (AD), suggesting that an insufficiency of ceramides in the stratum corneum is an etiologic factor in atopic dry and barrier-disrupted skin. In this study, we investigated, as a possible mechanism involved in the ceramide deficiency, whether sphingomyelin (SM) metabolism is altered in AD as compared to normal controls. In stripped stratum corneum and biopsied whole epidermis of patients with AD, SM hydrolysis as measured at pH 4.7 using [choline-methyl-14C]sphingomyelin as a substrate were markedly increased by 27- and 7-fold, respectively. Radio-thin-layer chromatography of the reaction products revealed that, whereas the SM hydrolysis in age-matched normal controls were associated with sphingomyelinase (SMase) that degrades SM to yield ceramides and phosphorylcholine (PC), most of the SM hydrolysis detected in AD were attributable not to the SMase but to a hitherto undiscovered epidermal enzyme, SM acylase, which releases free fatty acid and sphingosyl-PC (Sph-PC) instead of ceramides. The potential of this acylase-like enzyme to generate Sph-PC through SM hydrolysis was corroborated by thin-layer chromatographic analysis of the reaction products obtained using porcine kidney acylase, followed by high-performance liquid chromatography-mass spectrometry. Furthermore, Sph-PC was also detected by high-performance liquid chromatography-mass spectrometry after incubation of SM with atopic stratum corneum samples. On the other hand, the stratum corneum of patients with contact dermatitis or chronic eczema exhibited neither increased SM hydrolysis nor the generation of Sph-PC upon radio-thin-layer chromatographic analysis. These findings suggest that SM metabolism is altered in AD, resulting in a decrease in levels of ceramides, which could be an etiologic factor in the continuous generation of atopic dry and barrier disrupted skin observed in AD.

Amidohydrolases↗
PubMed1996

In vitro parathyroid hormone release in patients with secondary hyperparathyroidism.

BACKGROUND: The purpose of this study was to determine the precise endocrine characteristics of parathyroid function in secondary hyperparathyroidism (sHPT). METHODS: We examined the effects of extracellular ionized calcium (Ca2+) varying from 0.5 to 2.0 mM on parathyroid hormone (PTH) release in parathyroid cell suspensions using a mid-regional PTH assay. Cells were obtained from 26 patients with sHPT who were divided into two groups according to the type of hyperplasia they exhibited, either nodular (n = 16) or diffuse (n = 10). For comparison, we also analyzed data from nine patients with primary hyperparathyroidism (pHPT; adenomas). RESULTS: Significant in vitro suppression of PTH release by Ca2+ was observed in the majority of subjects, regardless of the histologic abnormality. The pHPT group exhibited no significant relationship between clinical and in vitro data. In contrast, in the sHPT group (taken as a whole), suppression of PTH release by Ca2+ exhibited a plateau at a total serum calcium concentration of 2.5 mmol/L, and a parathyroid gland weight of 2 g. CONCLUSIONS: These findings suggest that there is a curvilinear relationship in sHPT, but not pHPT, between the in vitro calcium sensitivity of parathyroid cells and total serum calcium, as well as gland weight. The in vitro calcium sensitivity in sHPT remains constant when the total serum calcium concentration exceeds 2.5 mmol/L, or when the gland weight exceeds 2 g.

Adenoma↗
PubMed1996

Cell cycle arrest in the G2 phase induced by phorbol ester and diacylglycerol in vascular endothelial cells.

The role of protein kinase C (PKC) in vascular endothelial cell proliferation was investigated using human umbilical vein endothelial cells released from the G1/S border. Phorbol 12-myristate 13-acetate (PMA) caused G2 arrest because 1) when added to G2 cells, PMA inhibited subsequent cell division; 2) these growth-arrested cells did not show morphological features of mitotic cells; and 3) PMA did not interrupt mitosis in cells released from nocodazole-induced M phase arrest. 1-Oleoyl-2-acetyl-sn-glycerol (OAG) added repeatedly from G2 also inhibited mitosis. The activation of cdc2 kinase around the G2/M transition was suppressed by PMA and OAG. Although cdc2 was expressed in the presence of PMA, dephosphorylation of its tyrosine residue was inhibited by PMA. In parallel, the expression of cdc25B was suppressed by PMA. The total and the cdc2-associated amount of cyclin B were both reduced by PMA. These data suggested that the PKC pathway negatively regulates the G2/M transition and that the inhibition of cdc2 kinase by the reduction in the levels of cdc25B and cyclin B may contribute to this effect.

CDC2 Protein Kinase↗