Genotype distribution of the 46C/T polymorphism of coagulation factor XII in the Japanese population: absence of its association with ischemic cerebrovascular disease.
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Aged↗
Biomedical subjects
N Tanahashi
Publications and source records attributed to N Tanahashi.
Activated factor XII levels are dependent on factor XII 46C/T genotypes and factor XII zymogen levels, and are associated with vascular risk factors in patients and healthy subjects.
Coagulation factor XII (FXII) is activated on contact with various biologic surfaces, including subendothelial tissues and lipoprotein particles. Thus, the plasma level of activated FXII (XIIa) might represent vascular lesions or be a marker of abnormal lipid metabolism. A 46C/T polymorphism was recently described in the FXII gene close to the ATG translation initiation codon, which was associated with inter-individual variation of plasma FXII zymogen levels. The present paper reports the association of the 46C/T polymorphism with plasma XIIa levels in apparently healthy subjects, and in patients with ischemic cerebrovascular disease (CVD) and arteriosclerosis obliterans (ASO). XIIa levels were not significantly different between patients and controls, but were strongly dependent on XII 46C/T genotypes (2.07 +/- 0.81, 1.65 +/- 0.63, and 0.93 +/- 0.41 ng/ml for C/C, C/T, and T/T genotypes, respectively; P < 0.0001). This association was evident for each group studied (P < 0.0001 for CVD and controls; P= 0.0007 for ASO). There were positive correlations between plasma FXII clotting activity and XIIa levels. In a univariate analysis, XIIa correlated with total cholesterol, triglycerides, plasminogen activator inhibitor-1, and C-reactive protein (CRP), although the presence of conventional cardiovascular risk factors (male sex, smoking, hypertension, hypercholesterolemia, diabetes) did not significantly increase XIIa. Stepwise regression analyses revealed that the XII clotting activity had the strongest association with XIIa. In conclusion, XIIa levels depended on XII 46C/T genotype and correlated with some cardiovascular risk factors. Thus, the FXII genotype should be taken into consideration for interpretation of plasma XIIa levels.
Aged↗
A 35-year-old man with cerebral hemorrhage and pheochromocytoma: the second brain-dead organ donor in Japan.
A 35-year-old man was brought into the emergency room of Keio University Hospital by ambulance because of a sudden onset of coma. His Glasgow Coma Scale was 3 and his blood pressure 150/100 mmHg. CT scanning revealed a subcortical hemorrhage 8 cm in diameter. His respiration deteriorated rapidly, and an emergency craniotomy was performed for hematoma removal and cerebral decompression. Postoperatively the patient remained in a deep coma (GCS = 3) requiring respiratory support. The family presented an organ donor card previously signed by the patient, and brain death was confirmed in accordance with Japan's transplant law. As a result of two tests conducted six hours apart brain death was confirmed on the 5th postoperative day. With the family's consent, the donor's heart, kidneys and skin were removed for organ transplantation to be performed in other institutions. An autopsy was performed after the removal of the organs and skin. An extensive subgaleal hemorrhage was found in the left cerebral hemisphere, and microscopic examination revealed extensive necrosis with karyolysis of neuronal cells, but no viable neuronal cells were found in the cerebrum. The brain stem was marked by edema, hemorrhage, infarction necrosis and neuronal cell loss. The cerebellum was swollen and congested and showed autolysis of the granular layer. These findings suggested brain death syndrome with respirator brain. Other autopsy findings included a huge pheochromocytoma in the right adrenal gland, bilateral bronchopneumonia, liver congestion and fatty metamorphosis with four cavernous hemangiomas, and mild chronic lymphocytic thyroiditis. This patient was the second brain-dead organ donor and the first brain-dead patient to undergo postmortem examination in Japan.
Adrenal Gland Neoplasms↗
[Antithrombotic therapy in cerebral infarction].
Antithrombotic therapy for the acute stage of cerebral infarction consists of thrombolysis, anticoagulant therapy and antiplatelet therapy, and their indications depend on the clinicopathological type of lesion, time after onset, and severity of illness. Tissue plasminogen activator has been approved in the United States for use in cerebral infarction within 3 hours after onset. The usefulness of heparin as anticoagulant therapy at the acute stage of cerebral infarction was not proved by the International Stroke Trial due to hemorrhagic complication. A selective thrombin inhibitor (argatroban) is used in Japan for atherothrombotic cerebral infarction within 48 hours after onset. A selective thromboxane A2 synthetase inhibitor (sodium ozagrel) had been approved for cerebral thrombosis within 5 days after onset. Aspirin (160-300 mg/day) is effective, but slightly, in the acute stage of cerebral infarction by the International Stroke Trial and Chinese Acute Stroke Trial. To prevent recurrence of stroke in the chronic stage of cerebral infarction, antiplatelet therapy (with aspirin or ticlopidine) is used for atherothrombotic cerebral infarction, and anticoagulant therapy with warfarin for cardioembolic cerebral infarction.
Acute-Phase Reaction↗
Platelet adhesion to human brain microvascular endothelial cells in vitro. Observation with video-enhanced contrast microscopy.
Employing video-enhanced contrast (VEC) microscopy and perfusion systems, we examined whether platelets adhere directly to human brain microvascular endothelial cells (HBEC) in vitro after thrombin treatment and whether adenosine diphosphate (ADP) or thromboxane A2-stimulated platelets adhere directly to HBEC at a low flow state in vitro. HBECs were cultured on a coverglass and put in the observation chamber of VEC microscopy. Following pretreatment with human alpha-thrombin 1.0 units/ml (n = 8) for 20 min, thrombin was thoroughly washed out. Platelet rich plasma (PRP) was perfused over HBEC at a low shear rate of 10 s(-1) for 30 min. Platelets adhered directly to thrombin-treated HBEC. Activated platelets by ADP (2 microM, n = 8) or thromboxane A2 (U-46619 10 microM, n = 5) were perfused over HBEC for 30 min and washed out. Platelets also adhered directly to HBEC. However, platelets did not adhere to HBEC when PRP only (n = 6) was perfused over HBEC for 30 min and washed out. Platelet adhesion directly to HBEC following thrombin treatment or platelet activation may play a pivotal role in secondary thrombus formation and microcirculatory disturbance in the ischemic brain.
Adenosine Diphosphate↗
Pathologic findings of silent hyperintense white matter lesions on MRI.
The pathologic features of silent hyperintense white matter lesions in T2-weighted images on MRI were studied in patients with no neurologic signs or symptoms. The small patchy hyperintense white matter lesions represented myelin pallor associated with vessels showing hypertension and arteriosclerotic changes. 'Caps' also showed myelin pallor with dilated perivascular spaces. There were no lacunar infarcts in these lesions. Some of 'caps' was shown to be elongated normal lateral ventricle. 'Rims' of early stage revealed subependymal gliosis that was a part of normal aging processes.
Aged↗
Transient vasodilatory effects of adrenomedullin on cerebral parenchymal microvessels in cats.
We studied the effects of adrenomedullin, structural homology of calcitonin gene-related peptide (CGRP), on the cerebral parenchymal microvessels in cats by our photoelectric method. Adrenomedullin significantly increased cerebral blood volume (CBV) at 0.5 and 1 min after intracarotid injection (0.01-1 nmol/kg, maximum; +0.71 vol% for 0.1 nmol/kg adrenomedullin). Adrenomedullin antagonist, adrenomedullin22-62 (0.01-10 nmol/kg), caused no significant changes in CBV and mean arterial blood pressure. Preinjection of 10 nmol/kg adrenomedullin22-52 blocked the vasodilatory effect of 0.01 nmol/kg adrenomedullin (P < 0.05). Pretreatment of 1 nmol/kg CGRP8-37, which has antagonistic activity against CGRP, also inhibited the vasodilatation of adrenomedullin. The degree of CBV reduction after adrenomedullin22-52 injection was greater than that after CGRP8-37 injection. Adrenomedullin has no major role in the maintenance of resting tone of intracerebral parenchymal vessels. Intravascularly administered adrenomedullin dilates cortical microvessels mainly through the specific adrenomedullin receptor.
Adrenomedullin↗
Oxygen and hydrogen gas transport through living C6 cell suspensions is faster than that in dead cells.
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Biological Transport↗
The proteasome-dependent proteolytic system.
The 20S proteasome is an intriguingly large complex that acts as a proteolytic catalytic machine. Accumulating evidence indicates the existence of multiple factors capable of regulating the proteasome function. They are classified into two different categories, one type of regulator is PA700 or PA28 that is reversibly associated with the 20S proteasome to form enzymatically active proteasomes and the other type including a 300-kDa modulator and PI31 indirectly influences proteasome activity perhaps by promoting or suppressing the assembly of the 20S proteasome with PA700 or PA28. Thus, there have been documented two types of proteasomes composed of a core catalytic proteasome and a pair of symmetrically disposed PA700 or PA28 regulatory particle. Moreover, the recently-identified proteasome containing both PA28 and PA700 appears to play a significant role in the ATP-dependent proteolytic pathway in cells, as can the 26S proteasome which is known as a eukaryotic ATP-dependent protease.
Adenosine Triphosphatases↗
ATP-Dependent inactivation and sequestration of ornithine decarboxylase by the 26S proteasome are prerequisites for degradation.
The 26S proteasome is a eukaryotic ATP-dependent protease, but the molecular basis of its energy requirement is largely unknown. Ornithine decarboxylase (ODC) is the only known enzyme to be degraded by the 26S proteasome without ubiquitinylation. We report here that the 26S proteasome is responsible for the irreversible inactivation coupled to sequestration of ODC, a process requiring ATP and antizyme (AZ) but not proteolytic activity. Neither the 20S proteasome (catalytic core) nor PA700 (the regulatory complex) by itself contributed to this ODC inactivation. Analysis with a C-terminal mutant ODC revealed that the 26S proteasome recognizes the C-terminal degradation signal of ODC exposed by attachment of AZ, and subsequent ATP-dependent sequestration of ODC in the 26S proteasome causes irreversible inactivation, possibly unfolding, of ODC and dissociation of AZ. These processes may be linked to the translocation of ODC into the 20S proteasomal inner cavity, centralized within the 26S proteasome, for degradation.
Adenosine Triphosphate↗
Pathologic findings of silent, small hyperintense foci in the basal ganglia and thalamus on MRI.
We analyzed the pathologic features of silent, small hyperintense foci in the basal ganglia and thalamus on MRI T2-weighted images (T2WI). Eight foci were histologically lacunar infarcts (LI), and 21 were dilated perivascular spaces (DPS). The foci with smooth margins were mostly DPS, whereas those with irregular margins were mostly LI (p = 0.018). Most putaminal foci were DPS, whereas most thalamic foci were LI (p = 0.001). The mean areas of LI and DPS overlapped below 19.6 mm2. The shape and site of hyperintense foci on T2WI are important for differentiating LI from DPS.
Aged↗
Contribution of proline residue for efficient production of MHC class I ligands by proteasomes.
Proteasomes are processing enzymes capable of generating major histocompatibility complex (MHC) class I ligands, but the mechanism of how they excise ligands without destroying them is largely unknown. Previously, we reported that most products of ornithine decarboxylase degraded in vitro by the 26 S ATP-dependent proteasome, which contained one or two Pro residues (Tokunaga, F., Goto, T., Koide, T., Murakami, Y., Hayashi, S., Tamura, T., Tanaka, K., and Ichihara, A. (1994) J. Biol. Chem. 269,17382-17385), which implied that the Pro residue has a role in the escape from random cleavage by proteasomes. Here, we examine the role of the Pro residue in producing MHC class I ligands in vitro. Proteasomes generated two cytotoxic T lymphocyte-epitopic precursor peptides, SIIPGLPLSL and DMYPHFMPTNL, from the 29-mer and 25-mer peptides harboring these sequences, which are derived from the c-akt proto-oncogene and the pp89 protein of mouse cytomagalovirus, respectively. Replacement of the first or second Pro residue within these epitopes by Ala resulted in a marked reduction of this epitope-derived production or their random cleavage by proteasomes, irrespective of the presence of PA28, which greatly accelerates the generation of unmodified ligands. Moreover, replacement of a single amino acid residue other than Pro in both epitopic and flanking regions by Ala or Leu had no or little appreciable effect on the SIIPGLPLSL or its derivative production. Thus, Pro residue(s) within these epitopic sequences presumably contributes to efficient production of MHC class I ligands through prevention of their random cleavage by proteasomes.
Amino Acid Sequence↗
Platelet adhesion to aortic endothelial cells in vitro after thrombin treatment: observation with video-enhanced contrast microscopy.
Secondary thrombus formation following arterial occlusion is suggested to play an important role in the exacerbation of ischemic organ damage. We investigated the effect of thrombin on endothelial cells from the aspect of morphological changes and induction of platelet adhesion to the endothelial cells. Using a video-enhanced contrast microscopy, we observed human aortic endothelial cells (HAEC) following perfusion of human alpha-thrombin of 1.0 U/ml (n = 7) or vehicle (n = 7) for 30 minutes. The endothelial cells began to shrink 15 minutes after thrombin administration. Gaps between the cells were formed. The cells became rearranged orderly in the same direction 30 minutes later. In another study, following pretreatment with human alpha-thrombin 1.0 U/ml (n = 10) or vehicle (n = 7) for 20 minutes and washout, platelets were perfused over HAEC for 30 minutes. Platelets adhered directly to thrombin-treated endothelial cells and became flat on the endothelial cells. Then other platelets were observed to approach to the flattened platelets and aggregated onto it. After washout of floating platelets, adhesion of platelets was further confirmed. These results suggest that thrombin may be involved in the endothelial damage and formation of platelet thrombi on the endothelial cells after blood flow disturbance.
Aorta↗
cDNA cloning and characterization of a human proteasomal modulator subunit, p27 (PSMD9).
We have employed cDNA cloning to deduce the complete primary structure of a new subunit, designated p27, of the modulator trimer complex that stimulates the association of the PA700 regulator with the catalytic 20S proteasome to form the ATP-dependent active 26S proteasome. We found two distinct cDNAs encoding two highly homologous proteins except in the C-terminal region, which are termed tentatively p27-1 and p27-2. The short p27-2 cDNA has a deletion of 65 bp near the 3'-end region of the long p27-1 cDNA, which encodes a large protein with an extended C-terminal region, designated p27-L, whereas the long p27-1 cDNA encodes a small protein named p27-S. The polypeptides of p27-L and p27-S consist of 223 and 209 amino acid residues with calculated molecular masses of 24,852 and 22,764 and isoelectric points of 6.50 and 5.28, respectively. Immunoblot analysis with anti-p27 antibody revealed that p27, together with two other ATPase components, TBP1 and p42, was associated with not only the modulator complex but also significantly with the 26S proteasome complex, suggesting that the three are common/sharing subunits in these two complexes. By the fluorescence in situ hybridization method, the p27 (PSMD9) gene was mapped to the q24.2-q24.3 band of human chromosome 12. Computer-assisted homology analysis revealed the high sequence similarities of p27-L with a possible counterpart in Caenorhabditis elegans and Saccharomyces cerevisiae whose function is yet unknown, the yeast gene that is here termed NAS2 (non-ATPase subunit 2). Disruption of NAS2 had no effect on cell viability, indicating that the subunit is not essential for proliferation of yeast cells.
Adenosine Triphosphatases↗
The proteasome is involved in angiogenesis.
The proteasome is a recently identified intracellular protease whose catalytic active site is a threonine residue and has been shown to play key roles in a variety of important intracellular events, including cell cycle progression, the antigen-presenting pathway, and apoptosis. However, its biological significance in multicellular organisms is still largely unknown because of lack of experimental systems for its study. Here we verified potential involvement of the proteasome in angiogenesis using lactacystin, a specific proteasome inhibitor. Lactacystin treatment resulted in almost complete prevention of in vivo neovascularization in the developing chick embryo chorioallantoic membrane. It also inhibited vascular endothelial tube formation on Matrigel, a model for in vitro angiogenesis, in a concentration-dependent fashion. Moreover, it prevented production of plasminogen activator, an important protease responsible for induction of angiogenesis, by endothelial cells, which correlated well with its suppression of intracellular proteasome activity. Our studies suggest that the proteasome operates in the process of angiogenesis, a phenomenon essential in important physiological and pathological settings.
Acetylcysteine↗
Chromosomal localization and immunological analysis of a family of human 26S proteasomal ATPases.
The 26S proteasome is a eukaryotic ATP-dependent protease functioning as a protein death machine. It is a large multisubunit complex, consisting of a catalytic 20S proteasome and two regulatory modules, named PA700. The PA700 complex is composed of multiple subunits of 25-110 kDa, which are classified into two subgroups, a subgroup of at least 6 ATPases that consitute a unique multi-gene family encoding homologous polypeptides conserved during evolution and a subgroup of approximately 15 non-ATPase subunits, most of which are structurally unrelated to each other. In the present study, we report the chromosomal localization and immunological properties of six members of the human 26S proteasomal ATPase family. By use of the fluorescence in situ hybridization method, the S4 (PSMC1), MSS1 (PSMC2), TBP1 (PSMC3), TBP7 (PSMC4), p45 (PSMC5), and p42 (PSMC6) genes were mapped to human chromosomes 19p13.3, 7q22.1-q22.3, 11p11.2, 19q13.11-q13.13, 17q23.1-q23.3, and 12q15, respectively, indicating that the genes for multiple ATPases of the 26S proteasome are located on different chromosomes. Immunoblot analysis revealed that all these ATPases were associated with the purified 26S proteasome and that some of them showed striking heterogeneity in their electrical charges.
Adenosine Triphosphatases↗
Hydrogen peroxide enhances phagocytic activity of ameboid microglia.
Microglia are considered to serve as a guardian of the brain. In achieving this task, they have been observed to transform into a reactive form and then an ameboid form. Several substances are implicated in the control of such behavior. We examined the effect of hydrogen peroxide on cultured microglia of ameboid form obtained from the fetal rat brain employing video-enhanced contrast-differential interference contrast microscopy. Microglia harvested from the culture bottle were observed to float in a spherical shape with abundant filopodia on the surface. However, on coming into contact with the glass surface of a cover slip, they immediately transformed into an ameboid form. The microglia spread themselves out, surrounded by thin transparent lammellipodia, which would not be clearly observable by either light microscopy or electron microscopy. In a concentration-dependent fashion, 10(-3)-10(-1) M hydrogen peroxide solution enhanced the ruffling process of the lamellipodia and formation of vesicles (phagosomes), which displayed a typical phagocytotic form. It is concluded that an increase in free radicals in ischemic tissue tends to facilitate the phagocytosis of ameboid microglia as macrophages.
Animals↗
cDNA cloning and functional analysis of p44.5 and p55, two regulatory subunits of the 26S proteasome.
We have employed cDNA cloning to deduce the complete primary structures of p44.5 and p55, two subunits of PA700, a 700-kDa multisubunit regulatory complex of the human 26S proteasome. These polypeptides consist of 422 and 456 amino acids with calculated molecular masses of 47463 and 52903, and isoelectric points of 6.06 and 7.56, respectively. Computer-assisted homology analysis revealed high sequence similarities of p44.5 and p55 with yeast proteins whose functions are yet unknown. Disruption of the yeast genes, termed NAS4 and NAS5 (non-ATPase subunits 4 and 5), resulted in lethality, indicating that each of the two subunits is essential for proliferation of yeast cells.
Amino Acid Sequence↗