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Biomedical subjects

Uichi Ikeda

Publications and source records attributed to Uichi Ikeda.

At least 37 records · Page 2Linked to original sources
PubMed2005

Mycophenolate mofetil prevents the development of experimental autoimmune myocarditis.

Experimental autoimmune myocarditis (EAM) is characterized by the appearance of multinucleated giant cells. EAM leads to severe myocardial damage and is a useful model of human giant cell myocarditis. We investigated whether mycophenolate mofetil (MMF), which is a potent immunosuppressant, prevents the development of myocarditis in a rat EAM model, and focused on the role of osteopontin (OPN) in the pathogenesis of this disorder. Adult Lewis rats were immunized with porcine cardiac myosin to establish EAM. The early MMF treatment completely prevented the development of EAM, and the late MMF treatment was also effective even against established EAM. Echocardiogram demonstrated that left ventricular function was also improved by the treatment with MMF. Real-time RT-PCR analysis showed that both early and late MMF treatments significantly inhibited myocarditis-induced OPN mRNA expression in the heart. Immunohistochemistry revealed that OPN expression was prominent in the myocardium on day 14, whereas expression was observed in the infiltrated macrophages on day 21. Mycophenolic acid (MPA) did inhibit agonist-induced OPN expression in cultured cardiomyocytes. These results show the therapeutic potential of MMF for autoimmune myocarditis and provide new insights into the pathogenesis of this disease.

Animals↗
PubMed2005

Effects of nicorandil on monocrotaline-induced pulmonary arterial hypertension in rats.

We investigated whether nicorandil might prevent and reverse monocrotaline (MCT)-induced pulmonary arterial hypertension. Rats were injected with 50 mg/kg of MCT subcutaneously and randomized to either 7.5 mg/kg/d of nicorandil in drinking water or placebo for 3 weeks. Animals that were treated with MCT and survived for 3 weeks were assigned to either nicorandil or placebo. Nicorandil markedly attenuated pulmonary arterial hypertension with severe structural remodeling of the pulmonary vessels. The survival rate at 3 weeks after treatment was significantly increased in the nicorandil group compared with the placebo group (73% versus 39%, P<0.05). In the placebo group, endothelial nitric oxide synthase (eNOS) protein was significantly decreased, the numbers of the CD45-positive cells and those of the proliferating cell nuclear antigen-positive cells were increased in the lung tissue, and P-selectin was intensely expressed on the endothelium of the pulmonary arteries. These features were prevented by nicorandil. Late treatment with nicorandil did not palliate established pulmonary arterial hypertension nor improved survival. Thus, nicorandil inhibited development of MCT-induced pulmonary arterial hypertension but failed to reverse it. These effects were associated with marked up-regulation of diminished lung eNOS protein along with improvement of pulmonary vascular endothelial activation and anti-inflammatory and anti-proliferative effects in the lung tissue.

Animals↗
PubMed2005

MCI-186 (edaravone), a free radical scavenger, attenuates hepatic warm ischemia-reperfusion injury in rats.

Hepatic warm ischemia-reperfusion injury (IRI) during hepatectomy and liver transplantation is a major cause of liver dysfunction in which the pathologic role of free radicals is a major concern. To assess the effect of MCI-186 (edaravone) on hepatic IRI, male Wistar rats were subjected to partial hepatic ischemia for 60 min after pretreatment with vehicle (group C) or MCI-186 (group M), or after both MCI-186 pretreatment and additional administration of MCI-186 12 h after reperfusion (group MX). Groups M and MX showed significantly lower levels of serum alanine aminotransferase and hepatic lipid peroxidation than group C, and also significantly lower expression levels of mRNA for cytokines, chemokines and intercellular adhesion molecule-1. There were fewer tissue monocytes and neutrophils in groups M and MX than in group C. These effects were more marked in group MX than in group M. Our findings suggest that treatment with MCI-186 attenuates hepatic IRI in this rat in vivo model.

Alanine Transaminase↗
PubMed2005

A critical increase in right-to-left shunt after acute myocardial infarction in a 68-year-old male with tetralogy of Fallot.

A male patient with tetralogy of Fallot accompanied by aortic regurgitation had maintained sufficient exercise capacity for a number of decades with the status of acyanotic tetralogy of Fallot. When he was 67 years old, he suffered a posterior wall acute myocardial infarction and direct percutaneous coronary angioplasty successfully revascularised the target lesion in the left circumflex artery. However, a few months after the onset of the myocardial infarction, his shortness of breath became clinically significant and was associated with increased right-to-left shunt and increased right ventricular end-diastolic pressure, as well as hypoxia. At 68 years old, therefore, total corrective repair of the tetralogy with replacement of the aortic and pulmonary valves was performed. The patient was asymptomatic after the successful operation. This report suggests that coronary artery disease can be one of the potential factors in inducing critical hemodynamic changes in aging patients with congenital heart disease, especially those who have a shunt between the right and left chambers. The unique clinical course is described with some discussion of the repair of tetralogy in adults.

Aged↗
PubMed2005

Repair of infarcted myocardium mediated by transplanted bone marrow-derived CD34+ stem cells in a nonhuman primate model.

Rodent and human clinical studies have shown that transplantation of bone marrow stem cells to the ischemic myocardium results in improved cardiac function. In this study, cynomolgus monkey acute myocardial infarction was generated by ligating the left anterior descending artery, and autologous CD34(+) cells were transplanted to the peri-ischemic zone. To track the in vivo fate of transplanted cells, CD34(+) cells were genetically marked with green fluorescent protein (GFP) using a lentivirus vector before transplantation (marking efficiency, 41% on average). The group receiving cells (n = 4) demonstrated improved regional blood flow and cardiac function compared with the saline-treated group (n =4) at 2 weeks after transplant. However, very few transplanted cell-derived, GFP-positive cells were found incorporated into the vascular structure, and GFP-positive cardiomyocytes were not detected in the repaired tissue. On the other hand, cultured CD34(+) cells were found to secrete vascular endothelial growth factor (VEGF), and the in vivo regional VEGF levels showed a significant increase after the transplantation. These results suggest that the improvement is not the result of generation of transplanted cell-derived endothelial cells or cardiomyocytes; and raise the possibility that angiogenic cytokines secreted from transplanted cells potentiate angiogenic activity of endogenous cells.

Animals↗
PubMed2005

[Deep vein thrombosis caused by pelvic lymphocyst following radical prostatectomy: a case report].

A 66-year-old man was admitted with distal edema of his right leg. He had undergone radical prostatectomy and pelvic lymphadenectomy for prostatic cancer 23 days previously. Abdominal computed tomography (CT) showed a lymphocyst (4.5 x 3.0 cm) along the right pelvic wall compressing the right external iliac vein. CT with contrast medium showed thrombus formation (about 9 cm) in the distal portion of the right external iliac vein and femoral vein. An inferior vena cava filter was placed to prevent pulmonary embolism, and anticoagulation with warfarin was started. One week later, CT showed shrinkage of the lymphocyst and thrombus in the vein, as well as a large thrombus trapped in the filter. Follow-up CT taken 2 months later revealed marked reduction of the lymphocyst and absence of thrombus in both the vein and filter. A lymphocyst, also known as a lymphocele, is a complication of radical pelvic surgery. Most lymphocysts are asymptomatic and regress spontaneously, but may lead to deep vein thrombosis and pulmonary embolism, usually a few weeks after surgery. Careful observation is needed even after discharge from hospital.

Aged↗
PubMed2005

[Liver regenerative therapy using glycoside-modified bone marrow].

Recent studies have reported that bone marrow cells (BMCs) have the ability to generate functional hepatocytes. However, the efficiency with which BMC transplantation generates functional hepatocytes is rather low. We assumed that if BMCs accumulated directly in liver, the functional BMC-derived hepatocytes should increase more efficiently. An attempt was made to increase the accumulation of BMCs directly in liver through the interaction between hepatic asialoglycoprotein receptor (ASGPR) and galactose-exposing BMCs. Galactose-exposing BMCs that expressed green fluorescent protein (GFP) were injected into Long-Evans-Cinnamon (LEC) rats, a Wilson's disease (WD) model, via the tail vein. The WD is an autosomal-recessive disorder characterized by impaired biliary copper excretion and copper toxicosis, all due to mutations in the atp7b gene. At 5 months after transplantation, GFP-expressing hepatocyte nodules accounted for 2.4% of total liver mass, and the normal ceruloplasmin was detectable in the sera of these LEC rats. These findings suggest that the functional BMC-derived hepatocytes can be generated and the new genes derived from BMCs, such as ATP7B and GFP, can be transferred to LEC rats by the direct accumulation of BMCs in liver without hematopoietic reconstitution in need of preparative lethal irradiation.

Animals↗
PubMed2004

The important role for betaVLDLs binding at the fourth cysteine of first ligand-binding domain in the low-density lipoprotein receptor.

The low-density lipoprotein (LDL) receptor (LDLR) is a crucial role for binding and uptaking apolipoprotein (apo) B-containing lipoproteins, such as very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL. The defect function of the LDLR causes familial hypercholesterolemia (FH), the phenotype of which is elevated plasma cholesterol and premature coronary heart disease (CHD). In the present study, we characterize the role of the cysteine residue of the ligand-binding domain of the LDLR. The mutant LDLR protein of cysteine for serine at codon 25 (25S-LDLR) was expressed in Chinese hamster ovary (CHO) cell line, ldl-A7. By Western blot analysis, the 25S-LDLR was detected with monoclonal antibody IgG-12D10, which reacts with the linker site of the LDLR but not with IgG-C7, which reacts with the NH2 terminus of the receptor. The 25S-LDLR bound LDL similarly to the wild-type LDLR, but the rate of uptake of LDL by the mutant receptor was only about half of that by the wild-type receptor. In contrast, the 25S-LDLR bound and internalized beta VLDL more avidly than LDL. These results suggest that the fourth cysteine residue of the first ligand-binding domain of the LDLR might be important for the internalization of atherogenic lipoproteins by vascular cells despite reduced LDL uptake, leading to atherosclerosis and premature cardiovascular disease.

Animals↗
PubMed2004

Cardiac function-related gene expression profiles in human atrial myocytes.

To obtain insights into the molecular pathogenesis of heart failure in humans, we have analyzed the expression profiles of>12,000 genes in a total of 17 human specimens of right atrial myocytes. From this large data set, we here tried to identify gene clusters, expression level of which is correlated precisely with clinical parameter values of cardiac function. We could reveal that cardiac myocytes with normal sinus rhythm were clearly differentiated, in the point of view of gene expression, from those with atrial fibrillation. Further, an expression profile-based prediction of arrhythmia by a newly developed "weighted-distance method" could efficiently diagnose our samples. We could even construct calculation formulae for the values of left ventricular ejection fraction based on the expression level of selected genes. To our best knowledge, this is the first report to indicate that pumping ability of heart can be predicted by any measures of atrium.

Adolescent↗
PubMed2004

Expression and induction of CYP3As in human fetal hepatocytes.

CYP3A4 and CYP3A7 mRNA expression levels were markedly up-regulated by dexamethasone (DEX), but not by rifampicin (RIF). CYP3A5 mRNA level was not increased significantly by DEX, RIF, or phenobarbital. Testosterone 6beta-hydroxylase activity was induced to about 2-fold of control by DEX. However, concomitant treatment with RIF did not alter DEX-mediated induction of CYP3A mRNA expression and testosterone 6beta-hydroxylase activity. DEX-mediated induction of CYP3A mRNA was suppressed in a dose-dependent manner by RU486, a glucocorticoid receptor (GR) antagonist. At 5microM RU486, DEX-mediated induction of CYP3A4, CYP3A5, and CYP3A7 mRNA expression was inhibited almost completely. These results suggest that, in human fetal hepatocytes, PXR is not involved in DEX-mediated induction of CYP3A4 and CYP3A7, and that the induction is mediated directly by GR.

Animals↗
PubMed2004

Increase in circulating endothelial progenitor cells after aortic aneurysm repair.

Rapid endothelialization of prosthetic vessels is essential to avoid fatal complications. We hypothesized that there may be mobilization of endothelial progenitor cells (EPCs) in patients who received aortic aneurysm repair, and measured the number of CD34-expressing EPCs (CD34(+) cells) in these patients. Blood samples were taken preoperatively, 6, 24, and 48 h, and 7 days after surgery in 13 patients with aortic aneurysm. Samples were also obtained from ten age-matched control subjects. The number of CD34(+) cells in the peripheral blood was quantified by flow cytometry. The levels of serum vascular endothelial growth factor (VEGF) were measured using an enzyme-linked immunosorbent assay kit. Baseline CD34(+) cell counts in the peripheral blood showed a tendency to be lower in patients with aortic aneurysm compared with healthy control subjects. The number of CD34(+) cells did not change over 48 h after aortic aneurysm repair; however, it had doubled by the 7th day. On the other hand, the baseline serum VEGF levels did not differ between the patients and control subjects. The VEGF levels increased gradually after vascular repair with a significant elevation after 48 h, which was followed by an increase in CD34(+) cell counts. In conclusion, the circulating CD34(+) cell counts and serum VEGF levels are increased after vascular prosthesis replacement in patients with aortic aneurysm, which might contribute to the rapid endothelialization of prosthetic vessels.

Antigens, CD34↗
PubMed2004

Matrix metalloproteinases and atherosclerosis.

Atherosclerosis is a major cause of coronary heart disease, and matrix metalloproteinases (MMPs) play an important role in atherosclerosis by degrading the extracellular matrix, which results in cardiovascular remodeling. Recent studies have identified enhanced expression of MMPs in the atherosclerotic lesion and their contribution to weakening of the vascular wall by degrading the extracellular matrix. The transcription, enzyme processing, and specific inhibition of MMPs by tissue inhibitors of matrix metalloproteinase (TIMPs) regulate these effects. These processes are also modified by inflammatory cytokines and cell-cell contact signaling. Both animal experiments and clinical sample analysis have shown that balance in expression and activation of MMPs and inhibition by TIMPs is critical for the development of stenotic and aneurysmal change. Polymorphism in the MMP gene promoter contributes to inter-individual differences in susceptibility to coronary heart disease. The development of therapeutic drugs specifically targeting MMPs may thus be useful for the prevention of atherosclerotic lesion progression, plaque rupture, and restenosis.

Animals↗
PubMed2004

Transcriptional profile of genes induced in human atrial myocardium with pressure overload.

BACKGROUND: The molecular response of human myocardium to mechanical stimuli, particularly the difference between pressure or volume overload cardiac hypertrophy, remains incompletely defined. METHODS: We investigated the transcriptional profile of genes induced in human pressure- or volume-overloaded myocardium with DNA microarray technology. We used right atrial tissue from patients who underwent cardiac surgery. On the basis of pressure data and echocardiographic findings, the patients were divided into three groups: control group (n=3), pressure overload group (mean right atrial pressure of >7 mm Hg, n=3), and volume overload group (moderate or severe tricuspid regurgitation, n=3). Expression profiles of 2139 human genes were investigated with mRNA obtained from the samples. RESULTS: In the pressure overload group, expression of genes of cyclin-dependent kinase inhibitor 1A (CDKI1A, 11.7+/-3.1-fold vs. control), and mitogen-activated protein kinase phosphatase-1 (MKP-1, 26.2+/-2.1-fold) was significantly increased compared with those in control or volume overload group (P<0.05). The specificity of these gene expressions was confirmed by a quantitative "real-time" polymerase chain reaction (PCR) analysis. In addition, mechanical strain induced CDKI1A and MKP-1 protein expressions in neonatal rat cardiac myocytes in an amplitude-dependent manner. In contrast, transcripts of growth factors did not significantly increase. CONCLUSIONS: This study demonstrated that gene expressions of CDKI1A and MKP-1, but not growth factors, are induced in chronic pressure-overloaded myocardium. These findings suggest that suppressors of the cell cycle or cell proliferation may play a critical role in the pathophysiology of pressure overload.

Adolescent↗
PubMed2004

Effective hepatocyte transplantation using rat hepatocytes with low asialoglycoprotein receptor expression.

Development of a reliable method of isolating highly proliferative potential hepatocytes provides information crucial to progress in the field of hepatocyte transplantation. The aim of this study was to develop reliable hepatocyte transplantation using highly proliferative, eg, progenitor-like hepatocytes, based on asialoglycoprotein receptor (ASGPR) expression levels for hepatocyte transplantation. We have previously reported that mouse hepatocytes with low ASGPR expression levels have highly proliferative potential and can be used as progenitor-like hepatocytes. We therefore fractionated F344 male rat hepatocytes expressing low and high levels of ASGPR and determined the liver repopulation capacity of hepatocytes according to low and high ASGPR expression in the liver. Next, 2 x 10(5) cells of each type were transplanted into female liver regenerative model dipeptidyl peptidase-deficient rats, and we estimated the rate of liver repopulation by the transplanted hepatocytes in the host liver, as determined by recognition of the Sry gene on the Y-chromosome. At 60 days after hepatocyte transplantation, the transplanted hepatocytes occupied approximately 76% of the total hepatocyte mass in the case of the transplantation of hepatocytes with low ASGPR expression, but accounted for approximately 12% and 17% of the mass in the case of the transplantation of hepatocytes with high ASGPR expression and unfractionated hepatocytes, respectively. In conclusion, these findings suggest that hepatocytes with low ASGPR expression can result in normal liver function and a high repopulation capacity in vivo. These results provide insight into development of a strategy for effective liver repopulation using transplanted hepatocytes.

Animals↗
PubMed2004

Gene transfer of nitric oxide synthase via the use of adeno-associated virus vectors.

Adeno-associated virus (AAV) is a replication-defective dependovirus and is not known to cause disease in humans. AAV vectors have a broad host range and can transduce both dividing and nondividing cells. Five primate AAV serotypes have been characterized in the literature and are designated as AAV types 1-5 (AAV1-5). There is divergence in homology and tropism for various AAV serotypes. AAV vectors can be produced by triple plasmids transfection system (adenovirus-free system) and purified by ultracentrifugation using CsCl gradient. The titer of AAV vectors is determined by dot-blot analysis. We have produced the AAV type 2 vectors encoding endothelial NOS (eNOS) gene and transduced rat aortic segments.

Animals↗
PubMed2004

[Inflammatory markers and cytokines in cardiovascular disease].

Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis and mediate the stages of atheroma development from initial leukocyte recruitment to eventual rupture of the unstable atherosclerotic plaque. Recent investigations demonstrated that several inflammatory markers are considered as new predictable risk factors for atherosclerosis and cardiac events. Among these markers, C-reactive protein (CRP) has been most widely studied. CRP is produced in the liver in response to interleukin-6 (IL-6), it is an acute phase reactant and used as a general inflammatory marker. High-sensitivity-CRP (hs-CRP) which could detect a small amount of CRP was recently developed, and numerous large-scale, prospective studies have found that elevated baseline levels of hs-CRP are independent predictor of cardiovascular events. Inflammatory cytokines such as IL-6 and tumor necrosis factor-alpha (TNF-alpha) have also been evaluated as potential tools for prediction of the cardiovascular events. In this review, we focused on the recent reports and potential use of the inflammatory markers and cytokines as a predictable tool for the cardiovascular events.

Arteriosclerosis↗