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Biomedical subjects

Yuji Matsuzawa

Publications and source records attributed to Yuji Matsuzawa.

At least 19 recordsLinked to original sources
PubMed2003

Matrix metalloproteinases as novel disease markers in Takayasu arteritis.

BACKGROUND: Takayasu arteritis (TA) is a chronic vasculitis that primarily affects large elastic arteries. Monitoring of disease activity is crucial because the disease tends to progress despite treatment with glucocorticoid and/or immunosuppressive agents. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) have generally been used as disease activity markers, but these are nonspecific inflammatory markers and lack the sensitivity and specificity to accurately monitor the disease status. Given the histological findings characterized by destruction of elastic fibers, we hypothesized that matrix metalloproteinases (MMPs) could be useful as markers of disease activity in TA. METHODS AND RESULTS: A consecutive series of 25 patients with TA were enrolled in this study. According to the National Institutes of Health criteria of disease activity, 11 were in an active phase and the remaining 14 were in remission. Circulating levels of MMP-2, MMP-3, and MMP-9 were determined by ELISA in all patients with TA and controls. MMP-2 levels were higher in patients with TA than in controls, but no correlation was found between serum MMP-2 and disease activity score. In contrast, MMP-3 and MMP-9 levels in patients with active disease were higher than in patients in remission and controls, and a positive correlation was demonstrated between circulating levels of MMP-3 or MMP-9 and disease activity score. The high levels of MMP-3 and MMP-9 improved when patients underwent remission. CONCLUSIONS: The present results indicate that MMP-2 can be helpful in diagnosing TA and that MMP-3 and MMP-9 can be used as activity markers for TA.

Adult↗
PubMed2003

Betacellulin and amphiregulin induce upregulation of cyclin D1 and DNA synthesis activity through differential signaling pathways in vascular smooth muscle cells.

Activation of EGF receptors is closely involved in vascular proliferative diseases. The signaling mechanisms of EGF ligands, including betacellulin (BTC) and amphiregulin (AR), are poorly understood. We examined how BTC and AR induced DNA synthesis activity in primary cultures of human thoracic aortic smooth muscle cells (HTASMCs). BTC induced phosphorylation of all four EGF receptors present on HTASMCs: ErbB1, ErbB2, ErbB3, and ErbB4. BTC rapidly induced the phosphorylation of Akt, GSK3alpha/beta, and two FoxO factors, FKHR and AFX, in a dose- and time-dependent manner. BTC increased nuclear beta-catenin accumulation. BTC increased cyclin D1 mRNA, cyclin D1 protein, and DNA synthesis activity. Pretreatment with the phosphatidylinositol 3'-kinase (PI 3'-kinase) inhibitor wortmannin suppressed BTC-induced cyclin D1 mRNA and protein and DNA synthesis activity. In contrast, AR, a specific ErbB1 ligand, induced sustained ERK1/2 and Elk1 phosphorylation, increased cyclin D1 mRNA and protein, and increased DNA synthesis activity. AR did not produce any changes in Akt phosphorylation. Pretreatment with PD98059 suppressed AR-induced cyclin D1 mRNA and protein. Thus, the PI 3'-kinase/Akt/GSK/FoxO/beta-catenin pathway could be the major signaling cascade for BTC-induced upregulation of cyclin D1 protein, whereas a sustained ERK/Elk1 activation could be the major signaling cascade for AR-induced upregulation of cyclin D1 protein in HTASMCs. Moreover, immunohistochemical staining revealed that that BTC, ErbB1, and ErbB4 are upregulated in the plaques of human atherosclerotic coronary arteries. Taken together, BTC and AR could be potent growth factors in proliferative vascular diseases.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2003

Association of hypoadiponectinemia with impaired vasoreactivity.

Endothelial dysfunction is a crucial feature in the evolution of atherosclerosis. Adiponectin is an adipocyte-specific plasma protein with antiatherogenic and antidiabetic properties. In the present study, we investigated the relation between adiponectin and endothelium-dependent vasodilation. We analyzed endothelial function in 202 hypertensive patients, including those who were not taking any medication. Forearm blood flow was measured by strain-gauge plethysmography. Plasma adiponectin level was highly correlated with the vasodilator response to reactive hyperemia in the total (r=0.257, P<0.001) and no-medication (r=0.296, P=0.026) groups but not with nitroglycerin-induced hyperemia, indicating that adiponectin affected endothelium-dependent vasodilation. Multiple regression analysis of data from all hypertensive patients revealed that plasma adiponectin level was independently correlated with the vasodilator response to reactive hyperemia. Vascular reactivity was also analyzed in aortic rings from adiponectin-knockout (KO) and wild-type (WT) mice. Adiponectin-KO mice showed obesity, hyperglycemia, and hypertension compared with WT mice after 4 weeks on an atherogenic diet. Endothelium-dependent vasodilation in response to acetylcholine was significantly reduced in adiponectin-KO mice compared with WT mice, although no significant difference was observed in endothelium-independent vasodilation in response to sodium nitroprusside. Our observations suggest that hypoadiponectinemia is associated with impaired endothelium-dependent vasorelaxation and that the measurement of plasma adiponectin level might be helpful as a marker of endothelial dysfunction.

Acetylcholine↗
PubMed2003

Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy.

OBJECTIVES: Adipocytokines, secreted by adipose tissue, may regulate fat metabolism, lipid and glucose homeostasis and insulin sensitivity. We analysed the relations between circulating concentrations of adiponectin, leptin, interleukin-6, tumor necrosis factor alpha and its soluble receptors sTNFR1 and R2, lipodystrophic phenotypes and metabolic alterations in patients under highly active antiretroviral therapy (HAART). METHODS: We studied 131 consecutive HIV-infected males under protease inhibitor (PI)-based HAART, with body mass index < 27 kg/m2 and C-reactive protein (CRP) < 10 mg/l. Patients were classified in four groups according to clinical examination: no lipodystrophy (NL), lipohypertrophy (LH), lipoatrophy (LA) and mixed lipodystrophy (ML). In addition to adipocytokines, we measured plasma fasting levels of triglycerides, cholesterol, cardiovascular risk markers (high-sensitivity CRP and apolipoproteins B/A1 ratio), fasted and 2 h post-glucose loading glycemia and insulinemia and calculated the quantitative insulin sensitivity check index. RESULTS: The patients were HIV-infected and PI-treated for a mean of 8.2 and 1.6 years respectively; 74% presented lipodystrophy, 38% altered glucose tolerance and 42% hypertriglyceridemia. Insulin sensitivity correlated positively with adiponectin and negatively with leptin and interleukin-6. Adiponectin, but not leptin, negatively correlated with all metabolic parameters. Insulin resistance, metabolic defects and cardiovascular risk markers were strongly negatively correlated with the adiponectin/leptin ratio (A/L), and positively with sTNFR1. LA patients had a longer duration of infection but ML patients presented the most severe metabolic alterations, insulin resistance and A/L decrease. CONCLUSIONS: These results suggest that adiponectin and the TNFalpha system are related to lipodystrophy, insulin resistance and metabolic alterations in patients under PI-based HAART. A/L and sTNFR1 could predict insulin sensitivity and potential cardiovascular risk in these patients.

Adiponectin↗
PubMed2003

Disturbed secretion of mutant adiponectin associated with the metabolic syndrome.

Adiponectin, an adipocyte-derived protein, consists of collagen-like fibrous and complement C1q-like globular domains, and circulates in human plasma in a multimeric form. The protein exhibits anti-diabetic and anti-atherogenic activities. However, adiponectin plasma concentrations are low in obese subjects, and hypoadiponectinemia is associated with the metabolic syndrome, which is a cluster of insulin resistance, type 2 diabetes mellitus, hypertension, and dyslipidemia. We have recently reported a missense mutation in the adiponectin gene, in which isoleucine at position 164 in the globular domain is substituted with threonine (I164T). Subjects with this mutation showed markedly low level of plasma adiponectin and clinical features of the metabolic syndrome. Here, we examined the molecular characteristics of the mutant protein associated with a genetic cause of hypoadiponectinemia. The current study revealed (1) the mutant protein showed an oligomerization state similar to the wild-type as determined by gel filtration chromatography and, (2) the mutant protein exhibited normal insulin-sensitizing activity, but (3) pulse-chase study showed abnormal secretion of the mutant protein from adipose tissues. Our results suggest that I164T mutation is associated with hypoadiponectinemia through disturbed secretion into plasma, which may contribute to the development of the metabolic syndrome.

Adiponectin↗
PubMed2003

Imatinib inhibits various types of activating mutant kit found in gastrointestinal stromal tumors.

Mutations of proto-oncogene c-KIT in gastrointestinal stromal tumors (GISTs) are considered to cause a constitutive activation of KIT responsible for their oncogenesis. Imatinib has therapeutic potential for GISTs because of its inhibitory effect on KIT kinase activity. To investigate the effect of Imatinib on various c-KIT mutations found in GISTs, we examined kinase activity of KIT, cell proliferation and tumorigenicity of transfectants with various c-KIT mutations. Murine lymphoid Ba/F3 cells transfected with one of the three types of mutants (KIT(del559-560), KIT(642Glu), and KIT(820Tyr)) or wild-type KIT were used for the experiments. Phosphorylation of KIT, mitogen-activated protein (MAP) and Akt was studied by immunoblotting with or without immunoprecipitation. In vitro studies on cell proliferation using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylcetrazolium bromide colorimetric assay and in vivo tumorigenicity assay using nude mice were also carried out. Imatinib could inhibit the KIT, MAP and Akt phosphorylation of all the transfectants but had a weaker effect on KIT(820Tyr). Imatinib potently inhibited the proliferation of cells transfected with KIT(820Tyr) at the concentration of 10 microM whereas it inhibited the other 3 types at 1 microM. Moreover, Imatinib could inhibit the tumor formation in nude mice transplanted with transfectants. In various types of activating mutant KIT, Imatinib could inhibit the constitutive activation of KIT signal transduction and cell proliferation both in vitro and in vivo although the effect of Imatinib on KIT(820Tyr) was weaker than that on KIT(del559-560) or KIT(642Glu).

Animals↗
PubMed2003

Measurement of fasting serum apoB-48 levels in normolipidemic and hyperlipidemic subjects by ELISA.

The present study was designed to evaluate the metabolism of chylomicron and chylomicron remnants by measuring serum apolipoprotein B-48 (apoB-48) levels in 335 normolipidemic and 253 hyperlipidemic subjects using a novel ELISA system. The distribution of fasting serum apoB-48 levels in normolipidemic subjects varied widely, ranging from <1 to >24 microgram/ml (mean, 5.2 +/- 3.8 microgram/ml; median, 3.9 microgram/ml). Serum apoB-48 levels correlated with serum triglyceride (TG) concentrations (r = 0.45, P < 0.001), but not with total cholesterol levels. Serum apoB-48 levels were 7 to 18 times higher in patients with Type I, Type V, and Type III hyperlipidemia, and only slightly higher in patients with Type IIa, Type IIb, and Type IV hyperlipidemia, compared with normolipidemic subjects. The calculated apoB-48/TG ratio was elevated only in patients with dysbetalipoproteinemia (apoE2/2 phenotype). In normolipidemic subjects, oral fat loading resulted in about 2-fold increase in serum apoB-48 levels, with a peak level recorded at 3-4 h postloading, and then returned to the baseline level within 6 h. On the other hand, in patients with dysbetalipoproteinemia, serum apoB-48 levels did not change considerably. Our results indicate that serum apoB-48 is a very useful parameter for evaluating lipoprotein metabolism in exogenous pathways.

Adult↗
PubMed2003

Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue.

BACKGROUND: High-sensitive C-reactive protein (hs-CRP) is a well-known risk factor for coronary artery disease (CAD). Recently, we have demonstrated that adiponectin served as an antiatherogenic plasma protein which was secreted specifically from adipocytes. The present study investigated the association between adiponectin and CRP in the blood stream and adipose tissue. METHODS AND RESULTS: We studied a total of 101 male patients, 71 of whom had angiographically documented coronary atherosclerosis. As a control group, 30 patients with normal coronary angiogram were included. The plasma hs-CRP levels were negatively correlated with the plasma adiponectin levels (r=-0.29, P<0.01). The plasma adiponectin concentrations were significantly lower and the hs-CRP levels were significantly higher in the CAD patients compared with control subjects. The mRNA levels of CRP and adiponectin were analyzed by quantitative real-time polymerase chain reaction method. We found that the CRP mRNA was expressed in human adipose tissue. A significant inverse correlation was observed between the CRP and adiponectin mRNA levels in human adipose tissue (r=-0.89, P<0.01). In addition, the CRP mRNA level of white adipose tissue in adiponectin deficient mice was higher than that of wild-type mice. CONCLUSIONS: The reciprocal association of adiponectin and CRP levels in both human plasma and adipose tissue might participate in the development of atherosclerosis.

Adiponectin↗
PubMed2003

Association of hypoadiponectinemia with coronary artery disease in men.

BACKGROUND: Adiponectin is an adipocyte-derived plasma protein that accumulates in the injured artery and has potential antiatherogenic properties. This study was designed to determine whether a decreased plasma adiponectin level (hypoadiponectinemia) can be independently associated with the prevalence of coronary artery disease (CAD). METHODS AND RESULTS: The consecutive 225 male patients were enrolled from inpatients who underwent coronary angiography. Voluntary blood donors (n=225) matched for age served as controls. Plasma adiponectin levels in the CAD patients were significantly lower than those in the control subjects. Multiple logistic regression analysis including plasma adiponectin level, diabetes mellitus, dyslipidemia, hypertension, smoking habits, and body mass index revealed that hypoadiponectinemia was significantly and independently correlated with CAD (P<0.0088). The entire study population was categorized in quartiles based on the distribution of plasma adiponectin levels. The interquartile cutoff points were 4.0, 5.5, and 7.0 microg/mL. The multivariate-adjusted odds ratios for CAD in the first, second, and third quartiles were 2.051 (95% confidence interval [CI], 1.288 to 4.951), 1.221 (95% CI, 0.684 to 2.186), and 0.749 (95%CI, 0.392 to 1.418), respectively. CONCLUSIONS: Male patients with hypoadiponectinemia (<4.0 microg/mL) had a significant 2-fold increase in CAD prevalence, independent of well-known CAD risk factors.

Adiponectin↗
PubMed2003

Localized relapse in bone marrow in a posttransplantation patient with t(6;9) acute myeloid leukemia.

We report a 38-year-old woman with t(6;9) acute myeloid leukemia who relapsed with localized leukemic cell growth in the bone marrow after she had undergone allogeneic bone marrow transplantation. The localized cell growth was first recognized by an apparent discrepancy in the DEK-CAN fusion transcript levels between the aspirates from the left and right iliac bone marrow. Magnetic resonance imaging of the iliac bone revealed localized cell accumulation in the left side. The nonhomogeneous and localized leukemic cell growth in this case may have been due to the graft-versus-leukemia effect following allogeneic transplantation with donor lymphocyte infusion. Serial monitoring of molecular markers for leukemia at different sites or magnetic resonance imaging of the bone marrow may be of value in detecting this type of relapse.

Adult↗
PubMed2003

A decreased number of c- kit-expressing cells in a patient with afferent loop syndrome.

Following gastrectomy, stasis in the afferent jejunal loop accompanied by an overgrowth of bacteria leads to a number of clinical symptoms, including the so-called afferent loop syndrome. The disturbances in intestinal motility may be related to stagnation of the intestinal contents in the afferent loop. The pacemaker cells for the basic contractile activity of the intestine are thought to be the interstitial cells of Cajal (ICCs). We and others have reported that ICCs express the c- kit receptor, and that a decreased number of c- kit-expressing ICCs is generally thought to result in disturbed intestinal motility. We report here a patient with postgastrectomy afferent loop syndrome with a decreased number of c- kit-expressing cells in the external muscle layer of the dilated intestine, suggesting damage to the ICCs.

Afferent Loop Syndrome↗
PubMed2003

Prevalence and phenotypic spectrum of cholesteryl ester transfer protein gene mutations in Japanese hyperalphalipoproteinemia.

A patient with cholesteryl ester transfer protein (CETP) deficiency presents with marked hyperalphalipoproteinemia (HALP). To investigate the contribution of CETP deficiency to the cause of HALP (HDL-C> or =1.94 mmol/l, 75 mg/dl), we investigated the CETP activities and the prevalence of genetic CETP mutations among 624 Japanese HALP subjects. The subjects were screened for four known genetic CETP mutations (intron 14 splicing defect (In14), exon 15 missense mutation (Ex15), intron 10 splicing defect (In10) and exon 6 nonsense mutation (Ex6)). We found the frequency of the patients with reduced CETP activity (<75% of normal controls) to be 55.5 and 64.1% in a high HDL group (1.94< or =HDL-C<2.59 mmol/l) and a marked HALP group (HDL-C> or =2.59 mmol/l, 100 mg/dl), respectively. At least one of the four mutations was identified in 65.7% of subjects with reduced CETP activities and 57.5% of subjects with marked HALP. The In14 and Ex15 mutations were very common in HALP subjects and the frequency of In10 mutation and Ex6 mutation was quite low. To investigate the impact of genetic CETP mutation on the phenotypes, we compared the plasma lipid levels and CETP activities between the subjects with two common mutations. All In14 homozygotes showed marked HALP, while marked HALP is less frequent (64.3%) in Ex15 homozygotes. HDL-C levels in Ex15 heterozygotes were significantly higher than those of In14 heterozygotes, suggesting the mutation has dominant negative effects on CETP activity in vivo. Some cases with In14 (5.7%) or Ex15 (7.2%) mutation showed low HDL-C levels. We conclude that CETP deficiency is a major cause of HALP; nevertheless CETP deficiency is not necessarily HALP.

Adult↗
PubMed2003

Atorvastatin markedly improves type III hyperlipoproteinemia in association with reduction of both exogenous and endogenous apolipoprotein B-containing lipoproteins.

Remnant lipoproteins are known to promote atherosclerosis especially in patients with type III hyperlipoproteinemia (HLP). In the current study, the effects of atorvastatin were investigated with special reference to the exogenous and endogenous apolipoprotein (apo) B-containing lipoprotein metabolism in type III HLP. Four Japanese male patients with type III HLP associated with homozygous apoE2 were studied. One-month administration of atorvastatin (20 mg once daily), after a 4-week dietary run-in, strikingly reduced serum total cholesterol and triglyceride (TG) levels by 52 (P<0.01) and 56% (P<0.05), respectively. Atorvastatin further decreased remnant-like particle (RLP)-cholesterol by 73% and RLP-TG by 65% (P<0.05), respectively. Distribution analysis by polyacrylamide gel disc electrophoresis clearly showed that atorvastatin diminished very low-, intermediate- and low-density lipoprotein particles. The relative particle diameter of intermediate-density lipoprotein became smaller after atorvastatin treatment (P<0.01). Furthermore, ultracentrifugal analysis demonstrated that atorvastatin significantly decreased cholesterol, TG and phospholipid concentrations in all apoB-containing lipoprotein fractions and very low-density lipoprotein (VLDL)-cholesterol/serum TG ratio (P<0.05), implying atorvastatin-induced reduction of beta-VLDL. Finally, newly developed assays of apoB-48 and apoB-100 revealed that atorvastatin markedly reduced these apolipoproteins by 43 and 52%, respectively (P<0.01), suggesting that atorvastatin decreased the number of both exogenous and endogenous apoB-containing lipoproteins. Taken together, atorvastatin improves remnant lipoprotein metabolism in type III HLP both in quality and in quantity. Atorvastatin can be one of the optimal options for the treatment of patients with type III HLP.

Aged↗
PubMed2003

Disappearance of intraglomerular lipoprotein thrombi and marked improvement of nephrotic syndrome by bezafibrate treatment in a patient with lipoprotein glomerulopathy.

Lipoprotein glomerulopathy (LPG) is a hereditary disorder characterized by intraglomerular lipoprotein thrombi and increased serum apolipoprotein (apo) E. Patients with LPG usually manifest with nephrotic syndrome, and some progress to renal failure; however, no effective therapeutic regimen has been established for this disease. We experienced a patient with LPG for whom bezafibrate treatment was very effective. This 30-year-old Japanese woman had nephrotic syndrome and type III hyperlipoproteinemia. Renal biopsy showed markedly dilated capillary lumina containing massive lipoprotein thrombi. Plasma apo E concentration was elevated to twice that of normal controls. She was proved to be a heterozygote of apo E2 Kyoto (Arg25Cys). After 2 years treatment with bezafibrate (400 mg/day), her plasma albumin gradually increased from 2.1 to 4.0 mg/dl, and intraglomerular lipoprotein thrombi disappeared almost completely. Bezafibrate decreased plasma apo E and dramatically increased high density lipoprotein (HDL)-cholesterol. The decrease in apo E was observed mainly in the pre-beta-fraction, not in the alpha fraction. Lipidological analyses of our patient suggest that the origin her lipoprotein thrombi may be mainly from pre-beta-lipoproteins and that HDL might be involved in resolving lipoprotein thrombi. Our case suggests that administration of fibrates such as bezafibrate may be a novel therapeutic strategy for resolving intraglomerular thrombi and improving nephrotic syndrome in patients with LPG.

Adult↗
PubMed2003

Decreased plasma adiponectin concentration in patients with essential hypertension.

Adipocytes secrete several biologically active substances that are presumed to be involved in obesity-related hypertension. There are no reports that deal with the relationship between plasma adiponectin concentration and blood pressure (BP). To evaluate the role of adiponectin in essential hypertension 33 patients with essential hypertensive (EHP) (12 women, 21 men) and 33 body mass index-matched normotensive healthy subjects (NHS) (13 women, 20 men) were studied. In EHP plasma adiponectin concentration was significantly lower than in NHS (9.1 +/- 4.5 v 13.7 +/- 5.2 microg/mL, respectively). In all subjects a significant negative correlation was found between plasma adiponectin concentration and mean, systolic, and diastolic BP, suggesting that adiponectin contributes to the clinical course of essential hypertension.

Adiponectin↗
PubMed2003

Pathophysiology of human genetic CD36 deficiency.

CD36, originally identified as glycoprotein IV on platelets, is an 88-kDa integral membrane protein that has multiple ligands and is expressed in the cardiovascular system (ie, blood vessel walls and the heart). Human genetic CD36 deficiency is relatively frequent in Asian and African populations. Investigation into the pathophysiology of this disorder has shown that CD36 may play an important role as a major scavenger receptor for oxidized low-density lipoproteins and as a crucial transporter for long-chain fatty acids. The CD36 deficiency may be related to the phenotypic expression of the "metabolic syndrome," which is frequently associated with atherosclerotic cardiovascular diseases. It also has been reported that CD36 deficiency might be linked with cardiomyopathy. These data raised the possibility that CD36 deficiency might be an important genetic background for these life-threatening human cardiovascular diseases.

Animals↗
PubMed2003

Angiotensin II stimulates the nuclear translocation of Smad2 and induces PAI-1 mRNA in rat hepatic stellate cells.

It has recently been reported that angiotensin II (ANGII) stimulates gene expression of transforming growth factor-beta1 (TGF-beta1) and is involved in hepatic fibrosis. This effect is thought to be caused through ANGII type 1 receptor (ATR1). However, a role of ANGII at the postreceptor levels of TGF-beta1 signaling has not been identified. To clarify the role of ANGII on hepatic fibrosis, we investigated the effect of ANGII on rat hepatic stellate cells (HSCs). HSCs were isolated from male Sprague-Dawley rats. TGF-beta1 and matrix protein gene expression in HSCs was assessed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) using SYBR Green I. The nuclear translocation of Smad2 in HSCs after 20 min ANGII stimulation was analyzed by Western blotting. ANGII was found to induce TGF-beta1 and matrix protein gene expression in HSCs. The nuclear translocation of Smad2 in HSCs was also induced by ANGII stimulation. These effects of ANGII were almost completely blocked by the ATR1 antagonist, CS-866. ANGII induces TGF-beta1 and matrix protein mRNA, and stimulates rapid nuclear translocation of Smad2 in rat HSCs through ATR1, which indicates that the ATR1 blockade represents a novel approach for the possible prevention of hepatic fibrosis.

Journal Article↗