Masako Mitsumata

Juntendo University, Tokyo, Tokyo-to, Japan

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Publications (74)221.78 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Uniform laminar shear stress (LS) and disturbed turbulent shear stress (DS) are thought to play opposite roles in preventing or inducing atherosclerosis. Endothelial cell (EC) growth and monocyte adhesion to ECs, an early event in atherosclerosis, are also oppositely regulated by LS and DS. However, how atherogenesis is affected by the regulation of growth by blood flow is unknown. Here we examined the role of p21(Sdi/Cip/Waf1) (p21), a growth inhibitor induced by LS, in monocyte adhesion to ECs. p21 was overexpressed by transfecting a p21-expressing adenoviral vector into ECs. Factors linking EC growth, monocyte adhesion, and p21 were examined by microarray analysis, PCR and Western blotting. Compared with DS, in the presence or absence of TNFalpha, LS significantly inhibited EC growth and monocyte adhesion to ECs. Both EC proliferation and monocyte adhesion induced by DS were inhibited by p21-overexpression. LS suppressed the expression of thioredoxin-interacting protein (TXNIP). Thioredoxin (TRX) activity, which is suppressed by TXNIP, was therefore higher under LS than DS, as reported previously. p21-overexpression significantly suppressed the DS-induced TXNIP expression, and inhibited the expression of vascular cell adhesion molecule 1 and chemokine (C-C motif) ligand 5 (CCL5/RANTES), which stimulates leukocyte recruitment and is downregulated by ROS scavenging. p21 may function to prevent atherogenesis by regulating the redox balance, which leads to the inhibition of adhesion molecule and chemokine expression in ECs under LS.
    Atherosclerosis 09/2010; 212(1):116-22. · 3.71 Impact Factor
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    ABSTRACT: To clarify the mechanism of atherosclerosis development in humans, we studied the mRNA and protein expression of PPAR subtypes in various types of atherosclerotic lesions and their correlation with cell proliferation and macrophage invasion. Human aortas were obtained from 35 autopsied cases, and each sample was divided into halves. One half was used for the analysis of mRNA or protein expression with RT-PCR or Western blotting, respectively. The other was microscopically classified into atheromatous plaque (AP), fatty streak (FS), and diffuse intimal thickening (DIT), and was analyzed immunohistochemically. The mRNA levels of both PPARs increased significantly in atherosclerosis and tended to increase in proportion to the severity of the lesion, and the expression of PPAR-alpha correlated with that of PPAR-gamma in FS and AP. The PPAR-gamma protein increased in AP. Monocytes/macrophages, as well as endothelial and smooth muscle cells, expressed the PPAR-gamma protein in plaques. This expression in the DIT was noted mainly in macrophages but was not correlated with the density of macrophages, suggesting that only certain macrophages express the PPARs in DIT. Cell proliferation did not correlate with PPARs expression in any lesion type. These findings suggest that PPARs may be associated with atheromatous plaque formation, and that PPAR-gamma may be involved in the early stages of human atherosclerosis.
    Pathology - Research and Practice 07/2010; 206(7):429-38. · 1.21 Impact Factor
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    ABSTRACT: We report a rare case of inflammatory pseudotumor/inflammatory myofibroblastic tumor (IPT/IMT) of the heart, involving the mitral valve. A 58-year-old woman presenting with dyspnea was immediately admitted to the hospital, and found to have congestive heart failure due to the invagination of a tumor-like mass of the mitral valve. This mass arose from and involved almost the entire posterior leaflet of the mitral valve and occupied almost the entire mitral valve orifice. The tumor was a yellowish-white well-circumscribed mass with a smooth surface. The excised mass was 3.0 x 2.3 x 1.8 cm, and consisted of abundant Sudan III-positive foam cells, histiocytes, lymphocytes, plasma cells, and loosely arrayed spindle cells, in vascular-rich fibrous tissue. Immunohistochemistry showed that the spindle cells were positive for vimentin and alpha-smooth muscle actin, and negative for desmin, CD34, and human muscle actin (HHF-35), suggesting they were myofibroblastic cells. The plasma cells and lymphocytes showed no monoclonality. There were few mitotic cells, and, except for the lymphocytes, few Ki-67-positive cells. The findings suggested IPT/IMT. The 39 cardiac IPT/IMT cases appearing in the English-language literature are discussed.
    Pathology International 07/2010; 60(7):533-7. · 1.72 Impact Factor
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    ABSTRACT: Remodeling of endothelial basement membrane is important in atherogenesis. Since little is known about the actual relationship between type IV collagen and matrix metalloprotease-2 (MMP-2) in endothelial cells (ECs) under shear stress by blood flow, we performed quantitative analysis for type IV collagen and MMP-2 in ECs under high shear stress. The mRNA of type IV collagen from ECs exposed to high shear stress (10 and 30 dyn/cm(2)) had a higher expression compared to ECs exposed to a static condition or low shear stress (3 dyn/cm(2)) (P < 0.01). (3)H-proline uptake analysis and fluorography revealed a remarkable increase of type IV collagen under high shear stress (P < 0.01). In contrast, zymography revealed that exposing to high shear stress, however similar positivity was leveled in the intracellular MMP-2 in the control and high shear stress-exposed ECs, reduced the secretion of MMP-2 in ECs. The results of Northern blotting, gelatin zymography and monitoring the intracellular trafficking of GFP-labeled MMP-2 revealed that MMP-2 secretion by ECs was completely suppressed by high shear stress, but the intracellular mRNA expression, protein synthesis, and transport of MMP-2 were not affected. In conclusion, we suggest that high shear stress up-regulates type IV collagen synthesis and down-regulates MMP-2 secretion in ECs, which plays an important role in remodeling of the endothelial basement membrane and may suppress atherogenesis.
    Cell and Tissue Research 06/2010; 340(3):471-9. · 3.68 Impact Factor
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    ABSTRACT: To evaluate the dose-response effects of granulocyte-colony stimulating factor (G-CSF) on atherosclerosis, we examined how G-CSF treatment at different concentrations affects atherosclerotic plaque formation in the aorta of cholesterol-fed rabbits. Japanese White rabbits (n=8 each) fed on a 1.5% cholesterol diet were subcutaneously injected with G-CSF at 50 (GL), 100 (GM), or 300 microg/kg/day (GH) for five days, or with 3 cycles of G-CSF at 100 microg/kg/day at 3-week intervals (GM3), or human serum albumin (Control). The extent and composition of atherosclerosis was evaluated 14 weeks after cholesterol feeding. Although G-CSF treatment did not affect plasma lipid levels, the percentage of aortic surface involvement in the GM3 group was significantly decreased (p<0.05) compared with the Control group. Histological analysis revealed that the intima media ratio was also diminished in GM and GM3 groups. The extent of intimal smooth muscle cell accumulation was higher in GL and GM3 groups than in the Control group. TIMP-2 mRNA expression in the aortic tissue was increased by G-CSF treatment. Our results suggest that appropriate doses of G-CSF reduced atherosclerotic plaque formation and increased plaque stability in cholesterol-fed rabbits.
    Journal of atherosclerosis and thrombosis 02/2010; 17(1):84-96. · 2.93 Impact Factor
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    ABSTRACT: A new antibody reacted with an epitope in Lp(a) that has undergone oxidation treatment, but is not present in native Lp(a), was developed. Thus, we determined serum oxidized Lp(a) concentration in healthy volunteers, and coronary artery disease (CAD), diabetes mellitus (DM), and hypertensive patients. We measured serum levels of oxidized Lp(a), Lp(a), LDL-cholesterol and HDL-cholesterol in 122 consecutive patients who underwent routine coronary angiography and had significant coronary artery stenosis (>75%), and 164 age-matched healthy volunteers. Moreover, serum native Lp(a), oxidized Lp(a) concentration, and pulse wave velocity (PWV) were determined in 181 hypertensive patients. Oxidized Lp(a) level in CAD patients with DM was significantly higher than in healthy volunteers (p<0.01). Moreover, serum oxidized Lp(a) concentration showed a significant positive correlation with pulse wave velocity, an index of arteriosclerosis (r=0.431, p<0.01). Of importance, the deposition of oxidized Lp(a) was readily detected in calcified areas of coronary arteries in patients with myocardial infarction. The present study demonstrated that oxidized Lp(a) may be a new risk factor for coronary artery disease. As the deposition of oxidized Lp(a) was detected in calcified areas of coronary arteries, oxidized Lp(a) might be implicated in endothelial dysfunction.
    Journal of atherosclerosis and thrombosis 09/2009; 16(4):410-8. · 2.93 Impact Factor
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    ABSTRACT: Our aim was to determine the roles of the ubiquitin (Ub)-proteasome system (UPS) in valvular diseases by immunohistochemically identifying Ub-positive cells in aortic and mitral valves and determining if Ub+cells were associated with the severity of valvular diseases. We evaluated surgically removed aortic and mitral valves from 60 patients (mean age, 64.5 years) for thickening, fibrosis, foam cell infiltration, thrombus, and atheromatous plaques by using grading scores. U+cells were detected immunohistochemically. We found Ub+cells in 16 (26.7%) of the 60 patients. Eleven (28.2%) of the 39 aortic valves and 5 (23.8%) of the 21 mitral valves were Ub-positive. Ub was found with granular depositions in the cytoplasm of monocyte-derived foam cells that were CD68+. The aortic valvular thickness of the Ub+group was significantly greater than that of the Ub- group (3.9+/-1.6mm vs. 3.2+/-1.6mm, p<0.05). Foam cells and fibrosis were greater in the Ub+group (p<0.05), and calcifications were prominent in aortic valves. There was no difference in the number of apoptotic cells in Ub+ and Ub- groups. Ub+cells were present in the affected valves and ubiquitinated proteins were accumulated in macrophage-derived foam cells. Ub+ foam cells are present in valves that are vulnerable to valvular disease, and UPS may contribute to the development of atherosclerosis through the inflammatory process.
    Journal of atherosclerosis and thrombosis 09/2009; 16(4):472-9. · 2.93 Impact Factor
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    ABSTRACT: We investigated lipid and lipoprotein abnormalities in SHRSP fatty rats as a new animal model of metabolic syndrome. We examined differentially expressed genes in the liver, one of the major tissues contributing to lipid metabolism. Using gel filtration high performance liquid chromatography, increased cholesterol concentrations of small particle size low-density lipoprotein (LDL) fractions were observed in SHRSP fatty rats, whereas the Zucker Fatty strain did not show a similar elevation of cholesterol content. Existence of apolipoprotein B in these fractions was confirmed by Western blotting. The small particle size of the LDL fractions was significantly decreased by a 4-week fenofibrate treatment. Microarray analysis identified seventeen genes that were significantly upregulated and ten that were significantly decreased in liver tissues of SHRSP fatty rats compared with levels in SHRSP rats. Stearoyl-coenzyme A desaturase 1, fatty acid synthase, ATP citrate lyase, and sterol regulatory element binding factor 1 genes were among the upregulated genes. These findings suggest that SHRSP fatty rats carry small dense LDL like particles which is a common lipid abnormality in the metabolic syndrome. Three of ten genes upregulated in liver tissues of SHRSP fatty rats play a role in this metabolic abnormality and are a therapeutic target of this metabolic syndrome.
    International Journal of Molecular Medicine 04/2009; 23(3):313-20. · 1.96 Impact Factor
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    ABSTRACT: Alpha-smooth muscle actin-positive endothelial cells have not been found in adult aortic endothelium except valve leaflets. Here, using en face immunostaining method, we identified alpha-smooth muscle actin-positive endothelial cells in the luminal surface of rat, mouse and human thoracic aortas. These cells express both endothelial markers and definite smooth muscle cell markers and were only occasionally observed in thoracic aorta of wild type mice and rats. Their density did not increase with aging. Given that alpha-smooth muscle actin-positive endothelial cells express low level of vascular endothelial-cadherin that is important for the maintenance of cell contact, these cells were frequently detected in the thoracic aorta of 5-week-old apolipoprotein-E deficient mice. In 20- to 24-week-old apolipoprotein-E deficient mice, marked accumulation of alpha-smooth muscle actin-positive endothelial cells was observed especially in the luminal surface of atheromatous plaques. Our findings indicate the existence of alpha-smooth muscle actin-positive endothelial cells in adult aortic endothelium and the possible association with progression of atherosclerosis.
    Biochemical and Biophysical Research Communications 04/2009; 380(3):620-6. · 2.41 Impact Factor
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    ABSTRACT: The Ubiquitin (Ub)-proteasome system maintains cellular homeostasis through proteolysis, and Ub appears in the damaged cells of many organs. Nonspecific interstitial pneumonia (NSIP)in elderly patients was studied to clarify the relationship between Ub-positive cells, cellular damage, and resistance to therapy. Specimens of surgical lung biopsy with the NSIP pattern (NSIP/P) from 13 patients (mean age, 68 years old) were examined histologically and immunohistochemically. Pneumocytes examined under high-power microscopy were counted for eosinophilic inclusion bodies and Ub-positive cells. NSIP/P was histologically evaluated and cases were scored for erosion and intraluminal granulation tissue subtypes (polypoid, mural, or occluded) as lung injury markers. NSIP/P was subdivided into cellular NSIP and fibrosing NSIP according to the proportions of interstitial inflammation and fibrosis. 1) Six of 13 patients with NSIP/P had Ub-positive cells (Ub+ group), and all inclusions identified by light-microscope were positive for Ub. A greater number of Ub+ pneumocytes were found compared with the inclusions by light-microscope, and Ub immunostaining was useful for the detection of the inclusions. 2) Granulation tissue scores in the Ub+ group were significantly greater than in the Ub- group (p<0.05); there was no difference in granulation tissue subtypes between the groups. 3) Granulation tissue scores in fibrosing NSIP/P (including each subtype) were significantly greater than in cellular NSIP/P. 4) After a follow-up period, there was no correlation between Ub+ group and NSIP therapy resistance or between the granulation tissue subtypes and therapy resistance. Some elderly patients with NSIP had inclusions, and these inclusions were Ub+. Pneumocyte injury might occur via the Ub-proteasome system pathway in elderly patients with NSIP/P, although there was no correlation between Ub+ pneumocytes and therapy resistance.
    Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 03/2009; 46(2):146-53.
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    ABSTRACT: Although transplantation of mononuclear cells (MNCs) induces angiogenesis in myocardial infarction, transplantation requires a large amount of bone marrow or peripheral blood cells. We examined the effects of transplantation of peripheral MNCs expressing an exogenous vascular endothelial growth factor (VEGF) gene in a pig model of acute myocardial infarction (AMI). MNCs were isolated from 20 ml peripheral blood from pigs and transfected with 10 microg of human VEGF165 plasmid (phVEGF). Myocardial infarction was induced by occlusion of the mid portion of the left anterior descending coronary artery (LAD) in anesthetized pigs. At 4 h after total occlusion, 5 x 10(6) VEGF-transfected MNCs were retrogradely transplanted into the pig via the coronary vein. Cardiac function, neovascularization and histology of the ischemic tissue were evaluated 4 weeks after transplantation. MNCs expressing hVEGF and infused via the coronary vein were efficiently delivered the heart in pigs with myocardial infarction. Transplantation of MNCs expressing hVEGF significantly increased left ventricular (LV) function, collateral vessels, and capillary density in heart from AMI model pigs. Transplantation of MNCs expressing hVEGF increased the wall thickness of the scar in the heart after AMI. Retrograde transplantation of peripheral blood MNCs expressing hVEGF efficiently induced angiogenesis and improved the impaired LV function in hearts of pigs with AMI. These findings indicate that angiogenic cells and gene therapy may be useful to treat ischemic heart disease.
    International journal of cardiology 02/2009; 142(1):56-64. · 6.18 Impact Factor
  • Atherosclerosis Supplements - ATHEROSCLER SUPPL. 01/2009; 10(2).
  • Atherosclerosis Supplements - ATHEROSCLER SUPPL. 01/2009; 10(2).
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    ABSTRACT: Adipose tissue-derived stem cells have been demonstrated to differentiate into cardiomyocytes and vascular endothelial cells. Here we investigate whether mature adipocyte-derived dedifferentiated fat (DFAT) cells can differentiate to cardiomyocytes in vitro and in vivo by establishing DFAT cell lines via ceiling culture of mature adipocytes. DFAT cells were obtained by dedifferentiation of mature adipocytes from GFP-transgenic rats. We evaluated the differentiating ability of DFAT cells into cardiomyocytes by detection of the cardiac phenotype markers in immunocytochemical and RT-PCR analyses in vitro. We also examined effects of the transplantation of DFAT cells into the infarcted heart of rats on cardiomyocytes regeneration and angiogenesis. DFAT cells expressed cardiac phenotype markers when cocultured with cardiomyocytes and also when grown in MethoCult medium in the absence of cardiomyocytes, indicating that DFAT cells have the potential to differentiate to cardiomyocyte lineage. In a rat acute myocardial infarction model, transplanted DFAT cells were efficiently accumulated in infarcted myocardium and expressed cardiac sarcomeric actin at 8 weeks after the cell transplantation. The transplantation of DFAT cells significantly (p < 0.05) increased capillary density in the infarcted area when compared with hearts from saline-injected control rats. We demonstrated that DFAT cells have the ability to differentiate to cardiomyocyte-like cells in vitro and in vivo. In addition, transplantation of DFAT cells led to neovascuralization in rats with myocardial infarction. We propose that DFAT cells represent a promising candidate cell source for cardiomyocyte regeneration in severe ischemic heart disease.
    Journal of Molecular and Cellular Cardiology 01/2009; · 5.15 Impact Factor
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    ABSTRACT: Embryonic stem (ES) cells have been proposed as candidates for cell replacement therapy in patients with intestinal failure because these cells can be expanded indefinitely without losing their pluripotent phenotype. We investigated the differentiation capacity of mouse ES cells into gut-like structures, including intestinal stem cells, and defined culture conditions for efficient induction of formation of these structures. ES cell-derived gut-like structures (ES-guts) were reproducibly induced in developing embryoid bodies (EBs) by day 21 of differentiation culture. ES-guts contained an endodermal epithelium, a smooth muscle layer, interstitial cells of Cajal, and enteric neurons and showed spontaneous contraction. Transplantation of ES-guts under the kidney capsules of immunodeficient mice induced formation of highly differentiated epithelium composed of absorptive cells and goblet cells in the grafts. Immunoreactivity for Musashi-1 (Msi-1), a marker of intestinal stem cells, was detected in 1.9% of the columnar epithelial cells in the graft. Culture with 0.1% dimethyl sulfoxide increased the numbers of ES-guts in EBs, and serum-replacement (SR) culture, in comparison to standard ES culture containing 15% serum, increased the area ratio of ES-guts to EBs. SR culture also promoted maturation of epithelium to form a single layer of columnar epithelial cells, including absorptive cells and goblet cells. Expression of Msi-1 mRNA and protein was significantly enhanced when EBs were cultured under SR conditions. In conclusion, SR conditions efficiently induce formation of ES-guts and promote differentiation of epithelium, including intestinal stem cells. These results suggest the feasibility of cell-based therapy for intestinal failure based on ES cell culture systems.
    Stem cells and development 09/2008; 18(1):113-26. · 4.15 Impact Factor
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    ABSTRACT: Benzo[a]pyrene (BaP), a polyaromatic hydrocarbon produced by the combustion of cigarettes and coke ovens, is a known procarcinogen. BaP activates the aryl hydrocarbon receptor (AhR) and induces the expression of a battery of genes, including CYP1A1, which metabolize BaP to toxic compounds. The possible role of CYP1 enzymes in mediating BaP detoxification or metabolic activation remains to be elucidated. In this study, we assessed the effects of CYP1 enzymes (CYP1A1, CYP1A2 and CYP1B1) on BaP-induced AhR transactivation and DNA adduct formation in HEK293 cells and HepG2 cells. Transfection of CYP1A1 and CYP1B1, but not CYP1A2, suppressed BaP-induced activation of AhR. Expression of CYP1A1 and CYP1A2, but not CYP1B1, inhibited DNA adduct formation in BaP-treated HepG2 cells. These results indicate that CYP1A1 and CYP1B1 play a role in deactivation of BaP on AhR and that CYP1A1 and CYP1A2 are involved in BaP detoxification by suppressing DNA adduct formation. BaP treatment did not induce DNA adduct formation in HEK293 cells, even after transfection of CYP1 enzymes, suggesting that expression of CYP1 enzymes is not sufficient for DNA adduct formation. Lower expression of epoxide hydrolase and higher expression of glutathione S-transferase P1 (GSTP1) and GSTM1/M2 were observed in HEK293 cells compared with HepG2 cells. Dynamic expression of CYP1A1, CYP1A2 and CYP1B1 along with expression of other enzymes such as epoxide hydrolase and phase II enzymes may determine the detoxification or metabolic activation of BaP.
    Toxicology and Applied Pharmacology 08/2008; 230(2):135-43. · 3.98 Impact Factor
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    ABSTRACT: This report describes Kawasaki disease (KD) in a rare autopsy case showing three uncommon phenomena: rapid aneurysmal development, ruptured giant aneurysm, and abscesses such as neutrophil aggregations, all contributing to the unpreventable sudden death of patients with KD. For a 5-year-old boy, KD was diagnosed on day 5 of his illness. His aneurysm was enlarged to a diameter of 18 mm on day 12, and the boy died on day 13. Aggregations of neutrophils containing myeloperoxidase and neutrophil elastase were scattered in chains over the aneurysmal wall of coronary artery, suggesting that destruction of the wall by an enzyme may have caused the rupture of the aneurysm.
    Pediatric Cardiology 07/2008; 29(6):1115-9. · 1.20 Impact Factor
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    ABSTRACT: To elucidate the pathogenic mechanism of polypoidal choroidal vasculopathy (PCV) based on histopathologic findings. Specimens obtained by surgical excision of PCV from five eyes of five patients (mean age, 75.6 +/- 3.1 years) were studied histopathologically. Immunohistochemical studies were also performed to identify CD34, vascular endothelial growth factor (VEGF), CD68, alpha-smooth muscle actin (alpha-SMA) and hypoxia-inducible factor (HIF)-1alpha. Hyalinization of choroidal vessels and massive exudation of fibrin and blood plasma were observed in all the specimens of PCV lesions. Some blood vessels were located above the RPE in two of the five eyes. Immunohistochemically, CD68-positive cells were detected around the hyalinized vessels. There were no alpha-SMA-positive cells in the vessels of PCV. CD34 staining showed endothelial discontinuity. Vascular endothelial cells within the PCV specimens were negative for VEGF. HIF-1alpha positive inflammatory cells were located in the stroma of specimens. Hyalinization of choroidal vessels, like arteriosclerosis, is characteristic of PCV.
    Investigative ophthalmology & visual science 07/2008; 49(11):4729-37. · 3.43 Impact Factor
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    ABSTRACT: The purpose of this study was to evaluate whether the spontaneously hypertensive rat SHRSP.Z-Lepr(fa)/IzmDmcr (SHRSP fatty) is a useful animal model to clarify molecular mechanisms that underlie metabolic syndrome. We investigated histopathologic changes in the cardiovascular organs and metabolic characteristics of SHRSP fatty rats, which are congenic rats from a cross between SHRSP and Zucker fatty (ZF) rats. The aortic wall and cardiac, carotid, and renal arteries from SHRSP and SHRSP fatty rats were thicker than those of ZF rats. The renal cortex in SHRSP and SHRSP fatty rats showed severe glomerulosclerosis. Pancreatic islands in SHRSP fatty and ZF rats showed marked hyperplasia. Steady-state plasma glucose concentrations were higher in SHRSP fatty than in ZF rats. Non-fasting triglyceride levels in SHRSP fatty rats were higher than in ZF rats. DNA synthesis in cultured vascular smooth muscle cells (VSMCs) from SHRSP fatty and SHRSP rats was significantly higher than that in VSMCs from Wistar-Kyoto (WKY) or ZF rats. Levels of platelet-derived growth factor A-chain and transforming growth factor-beta1 mRNAs were higher in VSMCs from SHRSP fatty and SHRSP than from ZF rats. Microarray analysis identified five genes that were significantly upregulated and four genes that were significantly downregulated in visceral adipose tissue of SHRSP fatty rats compared with levels in control strains (SHRSP and ZF rats). These findings suggest that the combination of hypertension and obesity accelerates vascular remodeling, dyslipidemia, and insulin resistance in metabolic syndrome. The phenotype of SHRSP fatty is similar to that of human metabolic syndrome, and therefore, studies of these rats may help clarify the molecular mechanisms that underlie metabolic syndrome in humans.
    Hypertension Research 06/2008; 31(5):1021-31. · 2.79 Impact Factor
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    ABSTRACT: We investigated the mechanisms of shear stress (SS)-induced activation of cytochrome P450 (CYP) 1A1 and cell cycle arrest with regard to the role of the aryl hydrocarbon receptor (AhR), since AhR mediates the expression of CYP1A1 induced by polycyclic aromatic hydrocarbons (PAHs) and is thought to be involved in the regulation of cell growth and differentiation. Human umbilical vein endothelial cells (ECs) were exposed to laminar SS and thereafter collected to evaluate the expression, activity, and transcription of CYP1A1 and the expression of AhR and cell cycle-related proteins. A physiological level of laminar SS (15 dynes/cm(2)) markedly increased the expression level and enzymatic activity of CYP1A1. SS stimulated CYP1A1 promoter activity without influencing mRNA stability. Loss of two functional xenobiotic response elements (XREs) in the 5'-flanking region of the CYP1A1 gene suppressed the SS-induced transcription of CYP1A1. Laminar SS stimulated the expression and nuclear translocation of AhR. alpha-Naphthoflavone, an AhR antagonist, and a small interfering RNA (siRNA) for AhR significantly suppressed SS-induced CYP1A1 expression. The siRNA also abolished SS-induced cell cycle arrest, the expression of the cyclin-dependent kinase inhibitor p21(Cip1), and dephosphorylation of retinoblastoma protein. Laminar SS stimulated the transcription of CYP1A1 through the activation of AhR in a way that is similar to the effects of PAHs. AhR was also involved in cell cycle arrest induced by SS. Our results suggest that sustained activation of AhR exposed to blood flow plays an important role in the regulation of EC functions.
    Cardiovascular Research 04/2008; 77(4):809-18. · 5.94 Impact Factor

Publication Stats

879 Citations
221.78 Total Impact Points

Institutions

  • 1995–2009
    • Juntendo University
      • • Department of Medicine
      • • Department of Internal Medicine
      Tokyo, Tokyo-to, Japan
  • 2008
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 2003
    • Nihon University
      • Department of Medicine
      Edo, Tōkyō, Japan
  • 2002–2003
    • University of Yamanashi
      • • Faculty of Medicine
      • • Division of Medicine
      Kōhu, Yamanashi, Japan
  • 2001
    • Fukuoka University
      Hukuoka, Fukuoka, Japan