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Biomedical subjects

Toru Kita

Publications and source records attributed to Toru Kita.

At least 37 records · Page 2Linked to original sources
PubMed2006

Risk of coronary events in Japanese patients with both hypercholesterolemia and type 2 diabetes mellitus on low-dose simvastatin therapy: implication from Japan Lipid Intervention Trial (J-LIT).

Hypercholesterolemic patients with type 2 diabetes mellitus are at increased risk of coronary heart disease (CHD); however, direct evidence is very limited in Japanese patients. The J-LIT is the first nationwide study conducted to assess the relationship between serum lipid levels and development of coronary events in Japanese hypercholesterolemic patients. We analyzed the coronary events in the J-LIT study subjects by having type 2 diabetes or not. Of the total 41,801 subjects without prior CHD who received open-label simvastatin, 5mg/day, 6554 (male 40.2%, age 57.8+/-7.8) subjects had type 2 diabetes, while 35,247 (male 30.0%, age 57.8+/-7.9) did not. In this analysis, relative coronary event risks based on a 0.26 mmol/l (10mg/dl) increase in low density lipoprotein-cholesterol (LDL-C), were similar between hypercholesterolemic subjects with and without type 2 diabetes (17.3% versus 19.4%). Although all subjects were treated with simvastatin, the subjects with type 2 diabetes have significantly more coronary events compared to the subjects without type 2 diabetes (1.80/1000 and 0.76/1000 patient-years, respectively). Given the results above, to reduce the risk of coronary events in Japanese patients with both hypercholesterolemia and type 2 diabetes, careful and strict cholesterol management is needed in addition to the control of blood glucose.

Adult↗
PubMed2006

Angiotensin II-dependent Src and Smad1 signaling pathway is crucial for the development of diabetic nephropathy.

Angiotensin II (Ang II) is known to play a pivotal role in the development of diabetic nephropathy. However, the precise mechanism of Ang II-mediated effects on diabetic nephropathy is still unknown. We have reported that Smad1 plays a key role in diabetic mesangial matrix expansion and directly regulates the transcription of type IV collagen (Col4) in vitro and in vivo. Here we examined the effect of Ang II on the expression of Smad1 and mesangial matrix expansion in streptozotocin (STZ)-induced diabetic rats in vivo, using Ang II type 1 receptor blocker, olmesartan. We also examined the signaling mechanism by which Ang II induces mesangial matrix expansion in vitro. Treatment of diabetic rats with low-dose olmesartan for 20 weeks reduced albuminuria and hyperfiltration without affecting blood pressure and inhibited mesangial matrix expansive changes and the expression of Col4 and smooth muscle alpha actin compared with those in untreated rats. Immunohistochemical staining and Western blotting showed that the increased expression of Smad1, phospho-Smad1, and phospho-Src was inhibited by olmesartan. Ang II induced Col4 synthesis and increased expression of phospho-Src and phospho-Smad1 in cultured mesangial cells, which was blocked by olmesartan. PP2, a Src tyrosine kinase inhibitor, and overexpression of dominant negative Src also reduced the phosphorylation of Smad1. Moreover, addition of small-interfering RNA against Src significantly reduced the phosphorylation of Smad1 and synthesis of Col4. Taken together, these results indicate that Ang II can regulate the development of mesangial matrix expansion in the early phase of diabetic nephropathy through Src and Smad1.

Angiotensin II↗
PubMed2006

Endovascular repair of a thoracoabdominal aortic aneurysm involving the celiac artery and the superior mesenteric artery.

We present a successful endovascular repair of a thoracoabdominal aortic aneurysm (TAAA) involving the celiac artery and the superior mesenteric artery. After the intentional occlusion of the celiac artery, an Inoue stent graft with a side arm to the superior mesenteric artery was implanted. Management of the visceral arteries in the endovascular repair of TAAA was highlighted.

Aged↗
PubMed2006

Serofendic acid, a novel substance extracted from fetal calf serum, protects against oxidative stress in neonatal rat cardiac myocytes.

OBJECTIVES: We examined whether serofendic acid (SFA) has protective effects against oxidative stress in cardiac myocytes. BACKGROUND: We previously identified a novel endogenous substance, SFA, from a lipophilic extract of fetal calf serum. Serofendic acid protects cultured neurons against the cytotoxicity of glutamate, nitric oxide, and oxidative stress. METHODS: Primary cultures of neonatal rat cardiac myocytes were exposed to oxidative stress (H2O2, 100 micromol/l) to induce cell death. Effects of SFA were evaluated with a number of markers of cell death. RESULTS: Pretreatment with SFA (100 micromol/l) significantly suppressed markers of cell death, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining and cell viability assay. Loss of mitochondrial membrane potential (DeltaPsi(m)) is a critical step of the death pathway, which is triggered by matrix calcium overload and reactive oxygen species. Serofendic acid prevented the DeltaPsi(m) loss induced by H2O2 in a concentration-dependent manner (with saturation by 100 micromol/l). Serofendic acid remarkably suppressed the H2O2-induced matrix calcium overload and intracellular accumulation of reactive oxygen species. The protective effect of SFA was comparable to that of a mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) channel opener, diazoxide. Furthermore, mitoK(ATP) channel blocker, 5-hydroxydecanoate (500 micromol/l), abolished the protective effect of SFA. Co-application of SFA (100 micromol/l) and diazoxide (100 micromol/l) did not show an additive effect. Thus, SFA inhibited the oxidant-induced mitochondrial death pathway, presumably through activation of the mitoK(ATP) channel. CONCLUSIONS: Serofendic acid protects cardiac myocytes against oxidant-induced cell death by preserving the functional integrity of mitochondria.

Animals↗
PubMed2006

Essential role of Hand2 in interventricular septum formation and trabeculation during cardiac development.

Interventricular septum (IVS) formation is one of the key events in the development of a four-chambered heart. We previously showed that the basic helix-loop-helix transcription factor Hand1 plays an important role in the formation of the IVS. Here, we found that the other Hand gene, Hand2, regulated expansion, trabeculation, and IVS formation in the embryonic heart. In transgenic embryos expressing Hand2 in the whole ventricles, the boundary region between the left and right ventricles expanded outwards, resulting in complete absence of the IVS. Moreover, trabecular formation was observed even in a region where the IVS was expected to form. In some transgenic embryos with heterogeneous expression of the transgene, a muscular septum did not form in a region where Hand2 was expressed, but an incomplete septum was identifiable in a region where Hand2 was not expressed, suggesting that septum formation was strictly regulated by the expression domain of Hand2. Furthermore, expression of trabecular markers including ANF, BNP, and connexin40 was significantly up-regulated in the ventricles of Hand2 transgenic embryos as well as in H9c2 cells over-expressing Hand2. These results suggested that the absence of Hand2 expression in the interventricular boundary region inhibits expansion and trabeculation in this area, contributing to the proper formation of the IVS.

Animals↗
PubMed2006

Activation of hypoxia-inducible factor 1 during macrophage differentiation.

Monocytes/macrophages of the myeloid lineage are the main cellular effectors of innate immunity. Hypoxia-inducible factor 1 (HIF-1) is essential for myeloid cell activation in response to inflammatory stimuli. However, it has not been established whether HIF-1 activity is induced during differentiation from monocyte to macrophage. We demonstrate that macrophage differentiation of THP-1 cells or monocytes from peripheral blood induces increased expression of both HIF-1alpha and HIF-1beta as well as increased HIF-1 transcriptional activity leading to increased expression of HIF-1 target genes. The increased HIF-1 activity in differentiated THP-1 cells resulted from the combined effect of increased HIF-1alpha mRNA levels and increased HIF-1alpha protein synthesis. Differentiation-induced HIF-1alpha protein and mRNA and HIF-1-dependent gene expression was blocked by treating cells with an inhibitor of the protein kinase C or MAP kinase signaling pathway. THP-1 cell differentiation was also associated with increased phosphorylation of the translational regulatory proteins p70 S6 kinase, S6 ribosomal protein, eukaryotic initiation factor 4E, and 4E binding protein 1, thus providing a possible mechanism for the modulation of HIF-1alpha protein synthesis. RNA interference studies demonstrated that HIF-1alpha is dispensable for macrophage differentiation but is required for functional maturation.

Alternative Splicing↗
PubMed2006

Histone acetyltransferase activity of p300 is required for the promotion of left ventricular remodeling after myocardial infarction in adult mice in vivo.

BACKGROUND: Left ventricular (LV) remodeling after myocardial infarction is associated with hypertrophy of surviving myocytes and represents a major process that leads to heart failure. One of the intrinsic histone acetyltransferases, p300, serves as a coactivator of hypertrophy-responsive transcriptional factors such as a cardiac zinc finger protein GATA-4 and is involved in its hypertrophic stimulus-induced acetylation and DNA binding. However, the role of p300-histone acetyltransferase activity in LV remodeling after myocardial infarction in vivo is unknown. METHODS AND RESULTS: To solve this problem, we have generated transgenic mice overexpressing intact p300 or mutant p300 in the heart. As the result of its 2-amino acid substitution in the p300-histone acetyltransferase domain, this mutant lost its histone acetyltransferase activity and was unable to activate GATA-4-dependent transcription. The two kinds of transgenic mice and the wild-type mice were subjected to myocardial infarction or sham operation at the age of 12 weeks. Intact p300 transgenic mice showed significantly more progressive LV dilation and diminished systolic function after myocardial infarction than wild-type mice, whereas mutant p300 transgenic mice did not show this. CONCLUSIONS: These findings demonstrate that cardiac overexpression of p300 promotes LV remodeling after myocardial infarction in adult mice in vivo and that histone acetyltransferase activity of p300 is required for these processes.

Animals↗
PubMed2006

Familial hemophagocytic lymphohistiocytosis with the MUNC13-4 mutation: a case report.

A 44-day-old male infant with familial hemophagocytic lymphohistiocytosis (FHL) associated with the MUNC13-4 mutation is reported. He presented with fever and poor feeding, lymphocytosis with thrombocytopenia and CSF pleocytosis without virological explanation. On the basis of progressive hyperferritinemia (1323 ng/ml), anemia (hemoglobin: 5.2 g/dl), hypertriglyceridemia (547 mg/dl) and increased LDH (1063 IU/l) with hemophagocytosis in the bone marrow, hemophagocytic lymphohistiocytosis was diagnosed. He showed a good response to corticosteroid therapy and the disease was stable for more than 5 months. Thereafter, he suffered from central nervous system complications, and successfully underwent unrelated cord blood stem cell transplantation. A remission was observed for more than 2 years, with mild mental retardation. Genetic analysis revealed that he had a compound heterozygous mutation of MUNC13-4; namely a novel 2163G>A mutation resulting in W721X, and 754-1G>C resulting in a premature stop codon in this gene. Western blot analysis showed the complete loss of the MUNC13-4 protein, whereas other molecules associated with the SNARE systems were detected at normal levels. Conclusion. FHL may have a broad clinical spectrum, and further analysis on its phenotype-genotype association is required to establish an appropriate treatment strategy, including immunochemotherapy and stem cell transplantation in the future.

CD8-Positive T-Lymphocytes↗
PubMed2006

Expression of lectin-like oxidized LDL receptor-1 in smooth muscle cells after vascular injury.

Lectin-like oxidized LDL receptor-1 (LOX-1) is an oxidized LDL receptor, and its role in restenosis after angioplasty remains unknown. We used a balloon-injury model of rabbit aorta, and reverse transcription-polymerase chain reaction revealed that LOX-1 mRNA expression was modest in the non-injured aorta, reached a peak level 2 days after injury, and remained elevated until 24 weeks after injury. Immunohistochemistry and in situ hybridization showed that LOX-1 was not detected in the media of non-injured aorta but expressed in both medial and neointimal smooth muscle cells (SMC) at 2 and 24 weeks after injury. Low concentrations of ox-LDL (10 microg/mL) stimulated the cultured SMC proliferation, which was inhibited by antisense oligonucleotides of LOX-1 mRNA. Double immunofluorescence staining showed the colocalization of LOX-1 and proliferating cell nuclear antigen in human restenotic lesion. These results suggest that LOX-1 mediates ox-LDL-induced SMC proliferation and plays a role in neointimal formation after vascular injury.

Animals↗
PubMed2006

Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy.

Diabetic nephropathy is the leading cause of end-stage renal disease, and glomerular mesangial matrix expansion is the hallmark in diabetic nephropathy. However, the precise mechanism for the development of mesangial matrix expansion has remained unknown. The key component involved in mesangial matrix expansion is type IV collagen (Col4). Recently, we have reported that Smad1 transcriptionally regulates expression of Col4 under diabetic conditions in vitro. Here we show that this direct regulator of Col4 also plays a crucial role for mesangial matrix expansion in vivo. Streptozotocin-induced diabetic rats are the model of incipient diabetic nephropathy, and showed various levels of mesangial matrix expansion at 24 weeks. The glomerular expression of Smad1 was significantly increased in diabetic rats with more mesangial matrix expansion by Western blot and immunohistochemical analysis. Furthermore, the glomerular expression of Smad1 was closely correlated with the glomerular expression of Col4 and smooth muscle alpha actin (alpha-SMA), while albuminuria or glomerular filtration rate was not correlated with mesangial matrix expansion. We also found that urinary excretion of Smad1 was closely associated with the severity of mesangial matrix expansion. In cultured mesangial cells expression of Smad1 upregulated the transcriptional activity of key molecules in mesangial matrix expansion, such as Col4 and alpha-SMA. These data indicate the critical involvement of Smad1 in mesangial matrix expansion in the early phase of diabetic nephropathy. Our data imply that urinary Smad1 might be a representative diagnostic marker for mesangial matrix expansion in diabetic nephropathy.

Actins↗
PubMed2006

Cardiac functional analysis by free-breath real-time cine CMR with a spatiotemporal filtering method, TSENSE: comparison with breath-hold cine CMR.

The aim of this study was to assess the accuracy of cardiac functional values obtained from free-breathing real-time cine CMR with the temporal sensitivity encoding (TSENSE) technique by comparing them with values obtained from conventional cine CMR. For the real-time cine CMR, two protocols were employed, one with good temporal resolution and one with good spatial resolution. The functional values obtained from the high temporal resolution real-time cine CMR agreed and correlated well with those of cine CMR. On the other hand, statistically significant but clinically slight overestimation of ESV (p < .05) and underestimation of EF (p < .01) were observed with the other protocol. Real-time cine CMR with TSENSE can provide acceptable cardiac functional values.

Aged↗
PubMed2006

Effects of MCI-186 (edaravone), a novel free radical scavenger, upon experimental atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND: Recent evidence suggests that oxidative stress may play a role in the development of atherosclerosis. MCI-186 (3-methyl-1-phenyl-1-phyrazolin-5-one, edaravone) is a novel free radical scavenger, but it remains unclear whether free radical scavengers would be effective for the prevention of the disease. METHODS AND RESULTS: Experimental atherosclerosis was induced in apolipoprotein E-deficient mice fed a high-fat diet containing 0.3% cholesterol. Mice were treated with an intraperitoneal injection of either MCI-186 1 mg/kg per day or MCI-186 10 mg/kg per day on alternate days over 4 weeks. Fatty streak lesion was suppressed by MCI-186 10 mg/kg per day administration, but not by mg/kg per day. Immunohistochemical analysis showed that macrophage and CD4+ T-cell accumulation and oxidative stress overload in the fatty streak lesion were suppressed in mice that received MCI-186 treatment. CONCLUSIONS: MCI-186 administration suppressed the development of atherosclerosis, associated with reduced expression of both immune-activated cells and oxidative stress in fatty streak plaques.

Animals↗
PubMed2006

Acute pleuropericarditis after coronary stenting: a case report.

A case of acute pleuropericarditis, which occurred after apparently successful percutaneous coronary intervention (PCI) for chronic total occlusion of the right coronary artery, is reported. The patient underwent coronary stenting without any immediate signs of complications. However, he had an acute onset of chest pain with fever which happened 4 h after PCI. He was diagnosed with acute pleuropericarditis by blood tests, electrocardiogram, chest X-ray, and echocardiogram. He rapidly recovered by intravenous hydrocortisone followed by oral prednisone administrations and percutaneous catheter pericardial drainage. Acute pleuropericarditis relevant to post-cardiac injury syndrome with an atypically early onset might have occurred in this case as a rare complication of PCI.

Acute Disease↗
PubMed2006

Gender difference in coronary events in relation to risk factors in Japanese hypercholesterolemic patients treated with low-dose simvastatin.

BACKGROUND: Gender differences between the risk factors for coronary heart disease and coronary events were examined in the Japan Lipid Intervention Trial, a 6-year observational study. METHODS AND RESULTS: Men (12,575) and women (27,013) were analyzed for risk of coronary events (acute myocardial infarction and sudden cardiac death). Simvastatin reduced serum low-density lipoprotein cholesterol (LDL-C) by 27% in both genders, and increased serum high-density lipoprotein cholesterol (HDL-C) in men (5%) and women (4%). The incidence of coronary events was lower in women (0.64/1,000 patient-years) than in men (1.57/1,000 patient-years). The risk of coronary events increased by 18% in men and 21% in women with each 10 mg/dl elevation of LDL-C, and decreased by 39% in men and 33% in women with each 10 mg/dl elevation of HDL-C. The risk increased proportionally with aging in women, but not in men. Diabetes mellitus (DM) was more strongly related to the risk of coronary events for women (relative risk 3.07) than for men (relative risk 1.58). CONCLUSIONS: The incidence of coronary events is lower in women. Serum LDL-C is related to an increased risk of coronary events to the same extent in both genders. DM seems to be a more important risk factor in women, trading off the lower risk of coronary events among them.

Adult↗