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Articles by T Shimizu
Total Records ( 6 ) for T Shimizu
  T Shimizu , T Tanaka , T Iso , H Doi , H Sato , K Kawai Kowase , M Arai and M. Kurabayashi

Objective— Vascular calcification is closely correlated with cardiovascular morbidity and mortality. Here, we demonstrate the role of Notch signaling in osteogenic differentiation and mineralization of vascular smooth muscle cells (SMCs).

Methods and Results— The Msx2 gene, a key regulator of osteogenesis, was highly induced by coculture with Notch ligand-expressing cells or overexpression of Notch intracellular domains (NICDs) in human aortic SMCs (HASMCs). Furthermore, the Notch1 intracellular domain (N1-ICD) overexpression markedly upregulated alkaline phosphatase (ALP) activity and matrix mineralization of HASMCs. A knockdown experiment with a small interfering RNA confirmed that Msx2 mediated N1-ICD–induced osteogenic conversion of HASMCs. Interestingly, Msx2 induction by N1-ICD was independent of bone morphogenetic protein–2 (BMP-2), an osteogenic morphogen upstream of Msx2. The transcriptional activity of the Msx2 promoter was significantly enhanced by N1-ICD overexpression. The RBP-Jk binding element within the Msx2 promoter was critical to Notch-induced Msx2 gene expression. Correspondingly, N1-ICD overexpression did not induce the Msx2 expression in RBP-Jk–deficient fibroblasts. Immunohistochemistry of human carotid artery specimens revealed localization of Notch1, Jagged1 and Msx2 to fibrocalcific atherosclerotic plaques.

Conclusion— These results imply a new mechanism for osteogenic differentiation of vascular SMCs in which Notch/RBP-Jk signaling directly induces Msx2 gene expression and suggest its crucial role in mediating vascular calcification.

  T Shimizu , S Inomata and M. Tanaka

Progesterone has long been known to have central effects, by reduced anaesthetic requirements as measured by minimum alveolar concentration (MAC) in various settings. However, other studies have contradicted these findings. Therefore, we compared the effect of progesterone on anaesthetic requirements in a mouse model.


Male C57BL/6 mice were treated with either progesterone (37.5 or 75 mg kg–1) or the olive oil vehicle, 1 h before each experiment. Animals were placed in a revolving cylinder (4 rev min–1) and supplied with oxygen and stepwise increasing concentrations of sevoflurane. The number of complete rollovers during revolution of the chamber was counted as a measure of anaesthetic requirement.


S.C. administration of progesterone 75 mg kg–1 significantly reduced sevoflurane requirement (P<0.0001). Progesterone 37.5 mg kg–1 did not change sevoflurane requirement.


We conclude that administration of exogenous progesterone injection at higher concentrations decreases anaesthetic requirement as defined by rolling response.

  S Inomata , T Maeda , T Shimizu , T Satsumae and M. Tanaka

Sevoflurane can be used as a sole agent for intubation in children, but studies have suggested that it is associated with emergence agitation. Fentanyl infusions can be used both to facilitate intubation and decrease emergence agitation. We investigated the effects of fentanyl on conditions at intubation and on emergence from sevoflurane anaesthesia without confounding nitrous oxide or premedication.


IRB approval and informed consent were obtained. Subjects comprised 150 ASA physical status I or II (age, 2–6 yr). Anaesthesia was induced with sevoflurane in oxygen and maintained using a predetermined concentration of sevoflurane. Subjects were randomly allocated to receive one of three doses of fentanyl: vehicle only (control group), a bolus dose of 1 µg kg–1 followed by a continuous infusion of 0.5 µg kg–1 h–1 (F1 group), or a bolus dose of 2 µg kg–1 followed by a continuous infusion of 1 µg kg–1 h–1 (F2 group). Sevoflurane minimum alveolar concentration for tracheal intubation (MACTI) and emergence agitation score were assessed.


MACTI values were 2.49%, 1.61%, and 1.16% in control, F1, and F2 groups, respectively (P<0.05). Agitation scores were 11.5, 7.0, and 2.6 in control, F1, and F2 groups, respectively (P<0.05).


Fentanyl infusion consisting of a bolus dose of 2 µg kg–1 followed by a continuous infusion of 1 µg kg–1 h–1 facilitates tracheal intubation and smooth emergence in children anaesthetized using sevoflurane.

Clinical trial registration: this study was started in 2000 and was finished in 2008. We had no registration number. IRB approval was obtained.

  C Nishitani , M Takahashi , H Mitsuzawa , T Shimizu , S Ariki , N Matsushima and Y. Kuroki

The role of MD-2 in cell surface expression of Toll-like receptor (TLR) 4 has been controversial. The purposes of this study were to characterize the N-glycan of TLR4 and to investigate the roles of MD-2 in N-linked glycosylation and cell surface expression of TLR4. Lectin blot and cell surface biotinylation revealed that TLR4 exhibited the 110 kDa protein with high mannose type N-glycans and the 130 kDa protein with complex type N-glycans and that only the 130 kDa TLR4 with complex type N-glycans was expressed on the cell surface. The cells transfected with a mutant TLR4C88A alone expressed only the 110 kDa TLR4 with a high mannose type N-glycan, which did not appear on the cell surface. However, TLR4C88A acquired complex type N-glycans and was expressed on the cell surface when MD-2 was co-transfected. The amount of the 130 kDa TLR4C88A with complex type N-glycans expressed on the cell surface depended on that of MD-2 transfected. -Mannosidase II inhibitor blocked the processing N-glycans to complex type, but TLR4 with high mannose type appeared on the cell surface, suggesting that TLR4 is destined to locate on the cell surface before processing N-glycans from a high mannose type to a complex type. From these results, we conclude that MD-2 is critical for cell surface expression of TLR4C88A. This study provides evidence that MD-2 possesses potential ability to play an essential role in cell surface expression of TLR4.

  M. S Lustgarten , Y. C Jang , Y Liu , F. L Muller , W Qi , M Steinhelper , S. V Brooks , L Larkin , T Shimizu , T Shirasawa , L. M McManus , A Bhattacharya , A Richardson and H. Van Remmen

In vitro studies of isolated skeletal muscle have shown that oxidative stress is limiting with respect to contractile function. Mitochondria are a potential source of muscle function-limiting oxidants. To test the hypothesis that skeletal muscle-specific mitochondrial oxidative stress is sufficient to limit muscle function, we bred mice expressing Cre recombinase driven by the promoter for the inhibitory subunit of troponin (TnIFast-iCre) with mice containing a floxed Sod2 (Sod2fl/fl) allele. Mn-SOD activity was reduced by 82% in glycolytic (mainly type II) muscle fiber homogenates from young TnIFastCreSod2fl/fl mice. Furthermore, Mn-SOD content was reduced by 70% only in type IIB muscle fibers. Aconitase activity was decreased by 56%, which suggests an increase in mitochondrial matrix superoxide. Mitochondrial superoxide release was elevated more than twofold by mitochondria isolated from glycolytic skeletal muscle in TnIFastCreSod2fl/fl mice. In contrast, the rate of mitochondrial H2O2 production was reduced by 33%, and only during respiration with complex II substrate. F2-isoprostanes were increased by 36% in tibialis anterior muscles isolated from TnIFastCreSod2fl/fl mice. Elevated glycolytic muscle-specific mitochondrial oxidative stress and damage in TnIFastCreSod2fl/fl mice were associated with a decreased ability of the extensor digitorum longus and gastrocnemius muscles to produce contractile force as a function of time, whereas force production by the soleus muscle was unaffected. TnIFastCreSod2fl/fl mice ran 55% less distance on a treadmill than wild-type mice. Collectively, these data suggest that elevated mitochondrial oxidative stress and damage in glycolytic muscle fibers are sufficient to reduce contractile muscle function and aerobic exercise capacity.

  K Yanagida , K Masago , H Nakanishi , Y Kihara , F Hamano , Y Tajima , R Taguchi , T Shimizu and S. Ishii

p2y5 is an orphan G protein-coupled receptor that is closely related to the fourth lysophosphatidic acid (LPA) receptor, LPA4. Here we report that p2y5 is a novel LPA receptor coupling to the G13-Rho signaling pathway. "LPA receptor-null" RH7777 and B103 cells exogenously expressing p2y5 showed [3H]LPA binding, LPA-induced [35S]guanosine 5'-3-O-(thio)triphosphate binding, Rho-dependent alternation of cellular morphology, and Gs/13 chimeric protein-mediated cAMP accumulation. LPA-induced contraction of human umbilical vein endothelial cells was suppressed by small interfering RNA knockdown of endogenously expressed p2y5. We also found that 2-acyl-LPA had higher activity to p2y5 than 1-acyl-LPA. A recent study has suggested that p2y5 is an LPA receptor essential for human hair growth. We confirmed that p2y5 is a functional LPA receptor and propose to designate this receptor LPA6.

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