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Biomedical subjects

Y Yazaki

Publications and source records attributed to Y Yazaki.

At least 505 records · Page 28Linked to original sources
PubMed1995

Effects of platelet-derived growth factor on the synthesis of lipoprotein lipase in human monocyte-derived macrophages.

Lipoprotein lipase (LPL), which is secreted by the two predominant cell types in atherosclerotic plaque, macrophages and smooth muscle cells, may be involved in atherosclerosis by generating atherogenic remnant lipoproteins. We investigated the effects of platelet-derived growth factor (PDGF)-BB on the synthesis of LPL by human monocyte-derived macrophages. These cells were cultured in the presence of PDGF-BB for 8 days, after which the enzyme activity, mass, and mRNA levels of LPL were determined. The effect of PDGF-BB was time-dependent and dose-dependent at concentrations of 1 to 10 ng/mL. At 10 ng/mL PDGF-BB enhanced twofold to 2.3-fold the secretion of LPL, and a pulse-labeling study with [35S]methionine revealed that 10 ng/mL PDGF-BB significantly increased the synthesis of LPL. Northern blotting analysis showed that the LPL mRNA level increased dose dependently in macrophages treated with PDGF-BB, and 10 ng/mL PDGF-BB enhanced twofold the expression of LPL mRNA. The protein kinase C inhibitor staurosporine suppressed the effect of PDGF-BB on LPL activity. These results indicate that PDGF-BB stimulated transcription of the LPL gene in human monocyte-derived macrophages through protein kinase C activation and resulted in an increased synthesis of LPL. Therefore, we hypothesize that the augmented synthesis of LPL by PDGF-BB modulates atherosclerosis by influencing lipoprotein metabolism in the vascular wall.

Becaplermin↗
PubMed1995

Inhibition of diet-induced atheroma formation in transgenic mice expressing apolipoprotein E in the arterial wall.

Apolipoprotein E (apoE) plays a crucial role in lipoprotein metabolism both in plasma and in peripheral tissues. To test whether apoE in the vascular wall has a direct and local effect on atherogenesis, we established transgenic mice expressing human apoE under control of H2 Ld promoter. Studies on mRNA levels and immunohistochemistry demonstrated that this line was characterized by high expression of human apoE in the arterial wall while its expression was relatively low in other tissues as compared with the respective endogenous expression of mouse apoE. They showed no difference in plasma cholesterol levels and lipoprotein profile from controls when fed both normal and atherogenic diets. However, after 24 wk of an atherogenic diet, the formation of fatty streak lesions in proximal aorta was markedly inhibited in transgenic mice as compared with controls. Both lesion area and esterified cholesterol content were < 30% of those in controls. In a tissue cholesterol labeling study with 3H-cholesterol, the specific activity of aorta cholesterol was much less in transgenic mice, suggesting that apoE enhances cholesterol efflux from the aortic wall into plasma. Thus, apoE has anti-atherogenic action which is mediated via enhancing reverse cholesterol transport from arterial wall.

Animals↗
PubMed1995

Induction of sustained expression of proto-oncogene c-fms by platelet-derived growth factor, epidermal growth factor, and basic fibroblast growth factor, and its suppression by interferon-gamma and macrophage colony-stimulating factor in human aortic medial smooth muscle cells.

Vascular medial smooth muscle cells migrate, proliferate and transform to foam cells in the process of atherosclerosis. We have reported that the intimal smooth muscle cells express proto-oncogene c-fms, a characteristic gene of monocyte-macrophages, which is not normally expressed in medial smooth muscle cells. In the present study, we demonstrated that combinations of platelet-derived growth factor (PDGF)-BB and either epidermal growth factor (EGF) or fibroblast growth factor (FGF) induced high expression of c-fms in normal human medial smooth muscle cells to the level of intimal smooth muscle cells or monocyte-derived macrophages, whereas c-fms expression by PDGF-BB alone was 1/10 and both EGF and FGF had no independent effect on c-fms expression. By contrast, interferon (IFN)-gamma and macrophage colony-stimulating factor (M-CSF) suppressed the induction of c-fms expression. These results indicate that multiple growth factors and cytokines may play a role in the phenotypic transformation of medial smooth muscle cells to intimal smooth muscle cells in atherosclerotic lesions by altering c-fms expression.

Aorta↗
PubMed1995

Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1.

Endothelin-1 (ET-1) is a 21-amino acid peptide with various biological activities including vasoconstriction and cell proliferation. To clarify the physiological and pathophysiological role of ET-1, we disrupted the mouse Edn1 locus encoding ET-1 by gene targeting and demonstrated that ET-1 is essential to the normal development of pharyngeal arch-derived tissues and organs. In this study, we focused on the phenotypic manifestations of Edn1-/- homozygous mice in the cardiovascular system. Edn1-/- homozygotes display cardiovascular malformations including interrupted aortic arch (2.3%), tubular hypoplasia of the aortic arch (4.6%), aberrant right subclavian artery (12.9%), and ventricular septal defect with abnormalities of the outflow tract (48.4%). The frequency and extent of these abnormalities are increased by treatment with neutralizing monoclonal antibodies or a selective ETA receptor antagonist BQ123. At an earlier embryonic stage, formation of pharyngeal arch arteries and endocardial cushion is disturbed in Edn1-/- homozygotes. In situ hybridization confirmed ET-1 expression in the endothelium of the arch arteries and cardiac outflow tract and the endocardial cushion as well as in the epithelium of the pharyngeal arches. Thus, ET-1 is involved in the normal development of the heart and great vessels, and circulating ET-1 and/or other ET isoforms may cause a functional redundancy, at least partly, through the ETA receptor.

Animals↗
PubMed1995

Characterization of rat GLUT5 and functional analysis of chimeric proteins of GLUT1 glucose transporter and GLUT5 fructose transporter.

To investigate the biological and biochemical properties of GLUT5, rat GLUT5 complementary DNA was transfected into Chinese hamster ovary cells. Rat GLUT5 was exclusively targeted to the plasma membrane and exhibited a transport activity, not for glucose, but for fructose. The affinity for fructose (Km = 11.6mM) was much higher than that of GLUT2, the other glucose transporter with fructose transport activity. Interestingly, rat GLUT5 was not photolabeled with 0.5 microM cytochalasin B, whereas a similar amount of GLUT1 was adequately photolabeled under the same experimental conditions. Next, to investigate the domains required for transport of glucose/fructose in GLUT1 and/or GLUT5, several chimeric GLUT1/GLUT5 proteins were expressed, and their glucose and/or fructose transport activities were studied. The intracellular middle loop and the region encompassing the membrane spanning domains 7-12 were observed to have crucial roles in GLUT1 glucose transport, whereas replacement of the N-terminal half or the intracellular C-terminal region with the corresponding region of GLUT5 produced no marked effects on glucose transport activity. In contrast, both the N-terminal half encompassing the region from the N-terminus through the 6th membrane spanning domain and the intracellular C-terminal region were mandatory for GLUT5 fructose transport. In conclusion, GLUT5 is a transporter exclusively for fructose and the structural requirements for fructose transport are more stringent than those for glucose transport among hexose transporter proteins.

Affinity Labels↗
PubMed1995

The role of the NPXY motif in the insulin receptor in tyrosine phosphorylation of insulin receptor substrate-1 and Shc.

The insulin receptor phosphorylates insulin receptor substrate-1 (IRS-1) and Shc on tyrosine residues, both of which associate with the protein-abundant Src homology/growth factor receptor-bound protein 2(ASH/GRB2) leading to p21ras activation. Juxtamembrane Tyr960 of the insulin receptor required for tyrosine phosphorylation of both IRS-1 and Shc is contained in the NPXY motif, which is also present in other tyrosine kinase receptors and oncogene products. In this study, the role of this motif in insulin's signaling was examined in Chinese hamster ovary cells expressing insulin receptors with mutations in this motif. All alterations in Tyr960 examined decreased tyrosine phosphorylation of both IRS-1 and Shc to a similar extent. The replacements of Asn957 and the deletion of NPE impaired tyrosine phosphorylation of Shc and IRS-1, although tyrosine phosphorylation of Shc was more severely affected than that of IRS-1. The amount of ASH/GRB2 bound to IRS-1 and Shc in vitro and in vivo was also decreased in these cells. These data suggest that the NPXY motif in the insulin receptor is important for tyrosine phosphorylation of both IRS-1 and Shc as well as subsequent signaling.

Amino Acid Sequence↗
PubMed1995

A rare case of cardiac sarcoidosis in a patient with progressive systemic sclerosis, Sjogren's syndrome, and polymyositis.

A 56-year-old woman with overlap syndrome of progressive systemic sclerosis (PSS), Sjogren's syndrome, and polymyositis is reported. She developed complete atrioventricular (AV) block and progressive bilateral hilar adenopathy, and was diagnosed as having sarcoidosis by histological examination of the hilar lymph nodes biopsied thoracoscopically. Although coexistence of one or two autoimmune diseases with sarcoidosis is not uncommon, coexistence of three or more autoimmune diseases with sarcoidosis is rare. To our knowledge, the described case is the first case in which the three above-mentioned autoimmune diseases were accompanied by myocardial sarcoidosis.

Cardiomyopathies↗
PubMed1995

Perforin-positive leukemic cell infiltration in the heart of a patient with T-cell prolymphocytic leukemia.

Here we report a rare case of T-cell prolymphocytic leukemia in whom leukemic killer cells, expressing a cytolytic factor perforin, infiltrated the heart. Perforin may have directly injured myocardial cells which showed marked expression of human leukocyte antigens (HLAs) and intercellular adhesion molecule-1 (ICAM-1) as well as costimulatory molecules B7 and B70, which are ligands for CD28 expressed on T-cells. In spite of chemotherapy against leukemic cells, this autoimmune process finally caused fatal congestive heart failure.

Adult↗
PubMed1995

Overexpression of apolipoprotein E prevents development of diabetic hyperlipidemia in transgenic mice.

To determine the role of apolipoprotein E (apoE) in diabetic hyperlipidemia, we induced diabetes in transgenic mice overexpressing apoE by intravenous injection of streptozotocin (STZ) and examined plasma lipoprotein metabolism in these mice. In STZ-induced diabetic mice, blood glucose levels were > 19 mmol/l (350 mg/dl) and plasma insulin levels were reduced to < 5 pmol/l (1 microU/ml). The diabetic nontransgenic mice developed hypercholesterolemia (plasma total cholesterol level: 4.55 +/- 1.32 vs. 1.97 +/- 0.13 mmol/l [176 +/- 51 vs. 76 +/- 5 mg/dl]) and hypertriglyceridemia (plasma triglyceride level: 0.82 +/- 0.29 vx. 0.42 +/- 0.11 mmol/l [73 +/- 26 vs. 37 +/- 10 mg/dl]) compared with values before induction of diabetes. In the diabetic nontransgenic mice, enhanced intestinal acylCoA:cholesterol acyltransferase activity was demonstrated, a factor that may contribute to the development of diabetic hyperlipidemia. Induction of apoE remarkably reduced the development of hyperlipidemia in diabetic transgenic mice compared with diabetic nontransgenic mice (plasma cholesterol level: 4.55 +/- 1.32 vs. 3.31 +/- 0.47 mmol/l [176 +/- 51 vs. 128 +/- 18 mg/dl], P < 0.01, and plasma triglyceride level: 0.82 +/- 0.29 vs. 0.17 +/- 0.11 mmol/l [73 +/- 26 vs. 15 +/- 10 mg/dl], P < 0.01). Plasma lipoprotein analysis by gel filtration chromatography showed that the reduction of plasma cholesterol and triglyceride levels was due to the disappearance of lipoproteins containing apoB. In these studies, we demonstrated the usefulness of STZ-induced diabetes in mice as an animal model for diabetic hyperlipidemia and demonstrated that endogenous induction of apoE in transgenic mice improved diabetic hyperlipidemia.

Animals↗
PubMed1995

Smooth muscle phenotypes in developing and atherosclerotic human arteries demonstrated by myosin expression.

Smooth muscle myosin heavy chains (MHC) exist in multiple isoforms. Rabbit smooth muscle contain at least three types of MHC isoforms; SM1 (204 kDa), SM2 (200 kDa) and SMemb (200 kDa). SM1 and SM2 are specific to smooth muscle, but SMemb is a nonmuscle-type MHC abundantly expressed in the embryonic aorta and in activated mesenchymal cells. We previously reported that these three MHC isoforms are differentially expressed in rabbit during normal vascular development and in experimental arteriosclerosis and demonstrated that MHC isoforms are excellent markers for smooth muscle phenotype. In order to clarify the clinical significance of MHC isoforms, this article will focus on the expression of smooth muscle MHC isoforms in normally developing and atherosclerotic human arteries, especially in coronary arteries. We recently isolated and characterized three cDNA clones encoding human SM1, SM2, and SMemb. The expression of SM2 mRNA in the human fetal aorta was significantly lower as compared to SM1 mRNA but the ratio of SM2- to SM1-mRNA was increased after birth. SMemb mRNA in the aorta was decreased after birth. Immunohistologically, SM1 was constitutively positive from the fetal stage to adulthood in the apparently normal media of the aorta and coronary arteries, whereas SM2 was not detected in fetal arteries of early gestational stage. SM2 was recognized in well-differentiated smooth muscle after perinatal stage. In the human aorta or coronary arteries, unlike in rabbit, SMemb was detected even in the adult. Mild diffuse intimal thickening in the major coronary arteries of the young was found to be composed of smooth muscle cells, reacting equally to three antibodies for MHC isoforms. In thickened but non-atheromatous intima, the expression of well-differentiated smooth muscle-specific MHC (SM2) was reduced, especially in the deeper layer. With progression of atherosclerosis, intimal smooth muscle diminished the expression of not only SM2 but also SM1, whereas alpha-smooth muscle actin was well preserved. We conclude from these results that smooth muscle MHC isoforms are important molecular markers for studying human vascular smooth muscle cell differentiation as well as the cellular mechanisms of atherosclerosis.

Amino Acid Sequence↗
PubMed1995

Role of apolipoprotein E in lipoprotein metabolism and in the process of atherosclerosis.

Apolipoprotein E (apoE) plays an important role in plasma lipoprotein metabolism through its high affinity binding to cell surface low density lipoprotein (LDL) receptor. To determine the role of apoE in plasma lipoprotein metabolism, transgenic mouse lines with integrated rat apoE gene under control of metallothionein promotor were established. The plasma level of rat apoE in homozygotes for the transgene was 17.4 mg/dl after zinc induction. In this group, plasma cholesterol and triglycerides levels were 43%, 68% reduced as compared with controls, respectively. Gel filtration chromatography showed that lipid reduction was mainly due to decreased both very low density lipoproteins (VLDL) and LDL. Furthermore, we studied the effects of apoE on the atherogenic process in Watanabe heritable hyperlipidemic (WHHL) rabbits. We administered 10 mg of purified apoE intravenously into five WHHL rabbits three times a week from their age of 2.5 months to 11 months for 8.5 months. After sustained administration of apoE, we found a significant reduction in the accumulation of cholesterol ester in aortae (1.55 +/- 0.07 mg/g tissue) as compared to control rabbits (4.32 +/- 0.61 mg/g tissue). Thus, apoE plays an important role not only in plasma lipoprotein metabolism but also in atherosclerotic process.

Animals↗
PubMed1995

Stimulation and priming of human neutrophils by IL-1 alpha and IL-1 beta: complete inhibition by IL-1 receptor antagonist and no interaction with other cytokines.

Together, interleukin-1 alpha (IL-1 alpha) and IL-1 beta primed human neutrophils for enhanced release of superoxide (O2-) stimulated by chemotactic peptide, chemokine, and plant lectin, and alone, each triggered O2- release in a dose-dependent manner. The maximal priming and triggering effect was obtained by high concentrations (50 to 500 ng/mL) of IL-1 alpha or IL-1 beta, though IL-1 beta was more effective than IL-1 alpha at suboptimal concentrations. Priming effect of IL-1 was very rapid and maximal within 10 minutes, whereas O2- release triggered by IL-1 was gradual and continued for 90 to 120 minutes. Combined stimulation of human neutrophils with IL-1 plus granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage CSF (GM-CSF) resulted in additive priming effect, and combined stimulation of neutrophils with IL-1 plus G-CSF, GM-CSF, or tumor necrosis factor (TNF) resulted in additive triggering effect, even when the maximal concentration of each cytokine was used. These priming and triggering effects of IL-1 alpha and IL-1 beta on the respiratory burst in human neutrophils were completely inhibited by IL-1 receptor antagonist (IL-1ra). Furthermore, only the net effect of IL-1 was inhibited by IL-1ra, even when human neutrophil was stimulated with IL-1 plus other cytokines to release O2-. Present results indicate that IL-1 does stimulate the respiratory burst activity in human neutrophils via receptor-mediated mechanism and suggest that the post-IL-1-receptor signaling pathways linked to the activation system of the respiratory burst are independent from those utilized by other cytokines in human neutrophils.

Adult↗
PubMed1995

[Smooth muscle myosin heavy chain expression in the arterial wall; a new viewpoint for vascular pathology].

Smooth muscle is an important component of the vessel wall. Smooth muscle cell undergoes phenotypic modulation during development of vascular lesions, such as atherosclerosis and restenosis following percutaneous transluminal coronary angioplasty (PTCA). In order to understand the mechanism of vascular remodeling, it is important to identify the smooth muscle cell in the vascular lesion and identify its phenotype by using molecular markers specific to the smooth muscle cell. Three types of myosin heavy chain (MHC) isoforms (SM1, SM2 and SMemb) expressed in smooth muscles are suitable for this purpose. In this study we first demonstrated that the expression of smooth muscle specific MHCs, such as SM1 and SM2, is reduced in human coronary arteries after the fifth decade. On the other hand, rapidly proliferating smooth muscles in the restenotic lesion express abundant SMemb but less amount of SM2. These observations indicate that deranged vascular smooth muscle differentiation is involved the development of vascular lesion. We furthermore demonstrated that smooth muscle-specific MHC is released into serum from the arterial wall following vascular damage as in dissecting aneurysm. Circulating smooth muscle MHC level was elevated 5-10 times above normal at 24 hours after aortic dissection as determined using a sensitive ELISA. We conclude from these results that smooth muscle MHC isoforms are important molecular markers for vascular pathology as well as for biochemical diagnosis of vascular injuries.

Aortic Dissection↗
PubMed1995

[Genetic linkage analyses of Romano-Ward syndrome (RWS) in 13 Japanese families].

Romano-Ward syndrome (RWS) is an autosomal dominant disorder characterized by prolongation of the electrocardiographic QT interval, with clinical manifestations that include recurrent syncope and sudden death from ventricular arrhythmias. In order to find a long QT locus in Japanese patients and to identify DNA markers useful for presymptomatic diagnosis, linkage analyses were undertaken in 13 Japanese families with RWS patients by means of two DNA markers located on 11p15.5. One of these marker loci, HRAS, was previously reported to be tightly linked to the LQT locus in another ethnic group. Our analyses of homogeneity suggest evidence for genetic heterogeneity of RWS with the Japanese population.

Adolescent↗
PubMed1995

Interaction of cardiac myocytes and non-myocytes in mechanical stress-induced hypertrophy.

It is known that mechanical stress directly changes the conformation of the functional proteins, or directly activates enzymes such as phospholipase in the plasma membrane. The integrin-cytoskeleton complex may be an alternative candidate structure for a mechanoreceptor and a transducer. The cytoskeleton has been also shown to play an important role in secretion. Mechanical stress may stimulate the secretion of some cytokines or angiotensin II, which may generate multiple intracellular signals as a secondary event. External stimuli are generally transduced into the nucleus through the activation of protein kinase cascade. Stretching of cardiac myocytes stimulates the activity of PKC, Raf-1 kinase, MAP kinase kinase. MAP kinase and S6 kinase. In cardiac myocytes, mechanical stress directly induces gene expression as well as protein synthesis. Immediate early genes are first induced, and then fetal-type genes are reinduced. Both in hypertrophied hearts and in the experimental model of cardiac hypertrophy induced by pressure overload. Ca(2+)-ATPase content of cardiac myocytes is depressed. Reduced function of sarcoplasmic reticulum causes insufficient decrease of intracellular calcium in diastole and induces slowing of ventricular relaxation. In the interstitium of pressure overloaded hearts, the accumulation of collagen fiber is increased. The abnormal deposit leads to increased chamber stiffness and diastolic dysfunction. Furthermore, TGF-beta and tissue renin-angiotensin system are up-regulated in pressure overloaded hearts, both of which accelerate the interstitial fibrosis.

Animals↗