Publications by authors named "Ryo Takeda"

30 Publications

  • Page 1 of 1

Investigations into the Potential of Using Open Source CFD to Analyze the Differences in Hemodynamic Parameters for Aortic Dissections (Healthy versus Stanford Type A and B).

Ann Vasc Surg 2021 Oct 12. Epub 2021 Oct 12.

Department of Cardiac Surgery, Asahikawa Medical University, Asahikawa, Japan.

Background: The objective of this study was to develop a method to evaluate the effects of an aortic dissection on hemodynamic parameters by conducting a comparison with that of a healthy (nondissected) aorta. Open-source software will be implemented, no proprietary software/application will be used to ensure accessorily and repeatability, in all the data analysis and processing. Computed tomography (CT) images of aortic dissection are used for the model geometry segmentation. Boundary conditions from literature are implemented to computational fluid dynamics (CFD) to analyze the hemodynamic parameters.

Methods: A numerical simulation model was created by obtaining accurate 3-dimensional geometries of aortae from CT images. In this study, CT images of 8 cases of aortic dissection (Stanford type-A and type-B) and 3 cases of healthy aortae are used for the actual aorta model geometry segmentation. These models were exported into an open-source CFD software, OpenFOAM, where a simplified pulsating flow was simulated by controlling the flow pressure. Ten cycles of the pulsatile flow (0.50 sec/cycle) conditions, totaling 5 sec, were calculated.

Results: The pressure distribution, wall shear stress (WSS) and flow velocity streamlines within the aorta and the false lumen were calculated and visualized. It was found that the flow velocity and WSS had a high correlation in high WSS areas of the intermittent layer between the true and false lumen. Most of the Stanford type-A dissections in the study showed high WSS, over 38 Pa, at the systole phase. This indicates that the arterial walls in type-A dissections are more likely to be damaged with pulsatile flow.

Conclusions: Using CFD to estimate localized high WSS areas may help in deciding to treat a type-A or B dissection with a stent graft to prevent a potential rupture.
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http://dx.doi.org/10.1016/j.avsg.2021.08.007DOI Listing
October 2021

Analysis of 3-D Kinematics Using H-Gait System during Walking on a Lower Body Positive Pressure Treadmill.

Sensors (Basel) 2021 Apr 8;21(8). Epub 2021 Apr 8.

Faculty of Health Sciences, Hokkaido University, Sapporo 060-0812, Japan.

Recently, treadmills equipped with a lower-body positive-pressure (LBPP) device have been developed to provide precise body weight support (BWS) during walking. Since lower limbs are covered in a waist-high chamber of an LBPP treadmill, a conventional motion analysis using an optical method is impossible to evaluate gait kinematics on LBPP. We have developed a wearable-sensor-based three-dimensional motion analysis system, H-Gait. The purpose of the present study was to investigate the effects of BWS by a LBPP treadmill on gait kinematics using an H-Gait system. Twenty-five healthy subjects walked at 2.5 km/h on a LBPP treadmill under the following three conditions: (1) 0%BWS, (2) 25%BWS and (3) 50%BWS conditions. Acceleration and angular velocity from seven wearable sensors were used to analyze lower limb kinematics during walking. BWS significantly decreased peak angles of hip adduction, knee adduction and ankle dorsiflexion. In particular, the peak knee adduction angle at the 50%BWS significantly decreased compared to at the 25%BWS ( = 0.012) or 0%BWS ( < 0.001). The present study showed that H-Gait system can detect the changes in gait kinematics in response to BWS by a LBPP treadmill and provided a useful clinical application of the H-Gait system to walking exercises.
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http://dx.doi.org/10.3390/s21082619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068341PMC
April 2021

Effects of unweighting on gait kinematics during walking on a lower-body positive-pressure treadmill in patients with hip osteoarthritis.

BMC Musculoskelet Disord 2021 Jan 8;22(1):46. Epub 2021 Jan 8.

Faculty of Health Sciences, Hokkaido University, Kita 12, Nishi 5, Kita-ku, Sapporo, 060-0812, Japan.

Background: Hip osteoarthritis (OA) is a musculoskeletal condition that makes walking difficult due to pain induced by weight-bearing activities. Treadmills that support the body weight (BW) reduce the load on the lower limbs, and those equipped with a lower-body positive-pressure (LBPP) device, developed as a new method for unweighting, significantly reduce pain in patients with knee OA. However, the effects of unweighting on gait kinematics remain unclear in patients with hip OA. Therefore, we investigated the effects of unweighting on kinematics in patients with hip OA during walking on a treadmill equipped with an LBPP device.

Methods: A total of 15 women with hip OA and 15 age-matched female controls wore a three-dimensional (3-D) motion analysis system and walked at a self-selected speed on the LBPP treadmill. Data regarding self-reported hip pain using a numeric rating scale (NRS) in which the scores 0 and 10 represented no pain and the worst pain, respectively, under three different BW conditions (100, 75, and 50%) were collected. Moreover, 3-D peak joint angles during gait under each condition were calculated and compared.

Results: In the hip OA group, the NRS pain scores at 50 and 75% BW conditions significantly decreased compared with that at 100% BW condition (50%, P = 0.002; 75%, P = 0.026), and the peak hip extension angle decreased compared with that in the healthy controls (P = 0.044). In both groups, unweighting significantly decreased the peak hip (P < 0.001) and knee (P < 0.001) flexion angles and increased the peak ankle plantar flexion angle (P < 0.001) during walking.

Conclusions: Unweighting by the LBPP treadmill decreased pain in the hip OA group but did not drastically alter the gait kinematics compared with that in the control group. Therefore, regarding the use of the LBPP treadmill for patients with hip OA, clinicians should consider the benefits of pain reduction rather than the kinematic changes.
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http://dx.doi.org/10.1186/s12891-020-03909-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792168PMC
January 2021

Chemotherapy-Induced IL8 Upregulates MDR1/ABCB1 in Tumor Blood Vessels and Results in Unfavorable Outcome.

Cancer Res 2020 07 14;80(14):2996-3008. Epub 2020 Jun 14.

Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.

Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TECs resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified. Here, we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues ( = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. , the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone. Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance. SIGNIFICANCE: These findings show that inhibition of ABCB1 in tumor endothelial cells may improve clinical outcome, where ABCB1 expression contributes to drug resistance and metastasis following first-line chemotherapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3791DOI Listing
July 2020

Influence of BMI on Gait Characteristics of Young Adults: 3D Evaluation Using Inertial Sensors.

Sensors (Basel) 2019 Sep 28;19(19). Epub 2019 Sep 28.

Department of Mathematical Sciences, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy.

Overweight/obesity is a physical condition that affects daily activities, including walking. The main purpose of this study was to identify if there is a relationship between body mass index (BMI) and gait characteristics in young adults. 12 normal weight (NW) and 10 overweight/obese (OW) individuals walked at a self-selected speed along a 14 m indoor path. H-Gait system, combining seven inertial sensors (fixed on pelvis and lower limbs), was used to record gait data. Walking speed, spatio-temporal parameters and joint kinematics in 3D were analyzed. Differences between NW and OW and correlations between BMI and gait parameters were evaluated. Conventional spatio-temporal parameters did not show statistical differences between the two groups or correlations with the BMI. However, significant results were pointed out for the joint kinematics. OW showed greater hip joint angles in frontal and transverse planes, with respect to NW. In the transverse plane, OW showed a greater knee opening angle and a shorter length of knee and ankle trajectories. Correlations were found between BMI and kinematic parameters in the frontal and transverse planes. Despite some phenomena such as soft tissue artifact and kinematics cross-talk, which have to be more deeply assessed, current results show a relationship between BMI and gait characteristics in young adults that should be looked at in osteoarthritis prevention.
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http://dx.doi.org/10.3390/s19194221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806343PMC
September 2019

Vulnerability analysis on the interaction between Asymmetric stent and arterial layer.

Biomed Mater Eng 2019 ;30(3):309-322

Division of Human Mechanical Systems and Design, Faculty of Engineering, Hokkaido University, Sapporo, Japan.

The utilization of Asymmetric stent for recovering atherosclerotic diseases, particularly non-symmetric obstruction, is a quite challenging breakthrough treatment. In terms of eccentric plaque, the non-uniform stiffness of arterial layer causes the increasingly complex issues of vulnerability. This study investigated the vulnerability of the interaction between the Asymmetric stent and the surrounding arterial layer using structural transient dynamic analysis in ANSYS. Four combinations of stent deployment, i.e. the Sinusoidal stent expanded by the offset balloon, the Sinusoidal stent expanded by the ordinary cylindrical balloon, the Asymmetric stent expanded by the offset balloon, and the Asymmetric stent expanded by the ordinary cylindrical balloon, are generated for this comparative study. Multilayer material properties from recent in vitro experiments are adopted for the surrounding arterial layer, such as a fibrous cap, lipid core, diseased-healthy intima, and diseased-healthy media. In order to address plaque vulnerability, the Cauchy stresses and Hencky strains are used for stress measure because of convenience in comparison with the uniaxial/biaxial tension test data. The location-specific threshold value from the diseased human carotid artery is adopted for rupture criteria. The simulation indicated that as regards the eccentric plaque, the plaque vulnerability is caused by the plaque shape and components rather than caused by the geometrical structure of the stent or balloon expansion method. Nevertheless, the non-symmetric inflation of balloon, which leads against the plaque, contributed to an increase in the vulnerability of fibrous cap of fibroatheroma plaque.
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http://dx.doi.org/10.3233/BME-191054DOI Listing
November 2019

Development of asymmetric stent for treatment of eccentric plaque.

Biomed Mater Eng 2018 ;29(3):299-317

Division of Human Mechanical Systems and Design, Faculty of Engineering, Hokkaido University, Sapporo, Japan.

The selection of stent and balloon type is decisive in the stenting process. In the treatment of an eccentric plaque obstruction, a symmetric expansion from stent dilatation generates nonuniform stress distribution, which may aggravate fibrous cap prone to rupture. This paper developed a new stent design to treat eccentric plaque using structural transient dynamic analysis in ANSYS. A non-symmetric structural geometry of stent is generated to obtain reasonable stress distribution safe for the arterial layer surrounding the stent. To derive the novel structural geometry, a Sinusoidal stent type is modified by varying struts length and width, adding bridges, and varying curvature width of struts. An end ring of stent struts was also modified to eliminate dogboning phenomenon and to reduce the Ectropion angle. Two balloon types were used to deploy the stent, an ordinary cylindrical and offset balloon. Positive modification results were used to construct the final non-symmetric stent design, called an Asymmetric stent. Analyses of the deformation characteristics, changes in surface roughness and induced stresses within intact arterial layer were subsequently examined. Interaction between the stent and vessel wall was implemented by means of changes in surface roughness and stress distribution analyses. The Palmaz and the Sinusoidal stent were used for a comparative study. This study indicated that the Asymmetric stent types reduced the central radial recoiling and the dogboning phenomenon. In terms of changes in surface roughness and induced stresses, the Asymmetric stent has a comparable effect with that of the Sinusoidal stent. In addition, it could enhance the distribution of surface roughening as expanded by an offset balloon.
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http://dx.doi.org/10.3233/BME-181737DOI Listing
September 2018

Gait characterization for osteoarthritis patients using wearable gait sensors (H-Gait systems).

J Biomech 2016 Mar 14;49(5):684-690. Epub 2016 Feb 14.

Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

The objective of this work was to investigate the possibilities of using the wearable sensors-based H-Gait system in an actual clinical trial and proposes new gait parameters for characterizing OA gait. Seven H-Gait sensors, consisting of tri-axial inertial sensors, were attached to seven lower limb body segments (pelvis, both thighs, both shanks and both feet). The acceleration and angular velocity data measured were used to estimate three-dimensional kinematic parameters of patients during level walking. Three new parameters were proposed to assess the severity of OA based on the characteristics of these joint center trajectories in addition to conventional gait spatio-temporal parameters. The experiment was conducted on ten subjects with knee OA. The kinematic results obtained (hip, knee and ankle joint angles, joint trajectory in the horizontal and sagittal planes) were compared with those from a reference healthy (control) group. As a result, the angle between the right and left knee trajectories along with that of the ankle joint trajectories were almost twice as large (21.3° vs. 11.6° and 14.9° vs. 7.8°) compared to those of the healthy subjects. In conclusion, it was found that the ankle joints during stance abduct less to avoid adduction at the knee as the severity of OA increases and lead to more acute angles (less parallel) between the right and left knee/ankle joints in the horizontal plane. This method was capable to provide quantitative information about the gait of OA patients and has the advantage to allow for out-of-laboratory monitoring.
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http://dx.doi.org/10.1016/j.jbiomech.2016.01.017DOI Listing
March 2016

Effects of plaque lengths on stent surface roughness.

Biomed Mater Eng 2015 ;25(2):189-202

Division of Human Mechanical Systems and Design, Faculty of Engineering, Hokkaido University, Sapporo, Japan.

The physical properties of the stent surface influence the effectiveness of vascular disease treatment after stent deployment. During the expanding process, the stent acquires high-level deformation that could alter either its microstructure or the magnitude of surface roughness. This paper constructed a finite element simulation to observe the changes in surface roughness during the stenting process. Structural transient dynamic analysis was performed using ANSYS, to identify the deformation after the stent is placed in a blood vessel. Two types of bare metal stents are studied: a Palmaz type and a Sinusoidal type. The relationship between plaque length and the changes in surface roughness was investigated by utilizing three different length of plaque; plaque length longer than the stent, shorter than the stent and the same length as the stent. In order to reduce computational time, 3D cyclical and translational symmetry was implemented into the FE model. The material models used was defined as a multilinear isotropic for stent and hyperelastic for the balloon, plaque and vessel wall. The correlation between the plastic deformation and the changes in surface roughness was obtained by intermittent pure tensile test using specimen whose chemical composition was similar to that of actual stent material. As the plastic strain is achieved from FE simulation, the surface roughness can be assessed thoroughly. The study found that the plaque size relative to stent length significantly influenced the critical changes in surface roughness. It was found that the length of stent which is equal to the plaque length was preferable due to the fact that it generated only moderate change in surface roughness. This effect was less influential to the Sinusoidal stent.
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http://dx.doi.org/10.3233/BME-151269DOI Listing
February 2016

The role of fibers in the femoral attachment of the anterior cruciate ligament in resisting tibial displacement.

Arthroscopy 2015 Mar 17;31(3):435-44. Epub 2014 Dec 17.

Department of Mechanical Engineering, Imperial College London, London, England; Musculoskeletal Surgery Group, Imperial College London School of Medicine, Charing Cross Hospital, London, England. Electronic address:

Purpose: The purpose was to clarify the load-bearing functions of the fibers of the femoral anterior cruciate ligament (ACL) attachment in resisting tibial anterior drawer and rotation.

Methods: A sequential cutting study was performed on 8 fresh-frozen human knees. The femoral attachment of the ACL was divided into a central area that had dense fibers inserting directly into the femur and anterior and posterior fan-like extension areas. The ACL fibers were cut sequentially from the bone: the posterior fan-like area in 2 stages, the central dense area in 4 stages, and then the anterior fan-like area in 2 stages. Each knee was mounted in a robotic joint testing system that applied tibial anteroposterior 6-mm translations and 10° or 15° of internal rotation at 0° to 90° of flexion. The reduction of restraining force or moment was measured after each cut.

Results: The central area resisted 82% to 90% of the anterior drawer force; the anterior fan-like area, 2% to 3%; and the posterior fan-like area, 11% to 15%. Among the 4 central areas, most load was carried close to the roof of the intercondylar notch: the anteromedial bundle resisted 66% to 84% of the force and the posterolateral bundle resisted 16% to 9% from 0° to 90° of flexion. There was no clear pattern for tibial internal rotation, with the load shared among the posterodistal and central areas near extension and mostly the central areas in flexion.

Conclusions: Under the experimental conditions described, 66% to 84% of the resistance to tibial anterior drawer arose from the ACL fibers at the central-proximal area of the femoral attachment, corresponding to the anteromedial bundle; the fan-like extension fibers contributed very little. This work did not support moving a single-bundle ACL graft to the side wall of the notch or attempting to cover the whole attachment area if the intention was to mimic how the natural ACL resists tibial displacements.

Clinical Relevance: There is ongoing debate about how best to reconstruct the ACL to restore normal knee function, including where is the best place for ACL graft tunnels. This study found that the most important area on the femur, in terms of resisting displacement of the tibia, was in the central-anterior part of the femoral ACL attachment, near the roof of the intercondylar notch. The testing protocol did not lead to data that would support using a large ACL graft tunnel that attempts to cover the whole natural femoral attachment area.
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http://dx.doi.org/10.1016/j.arthro.2014.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348375PMC
March 2015

Drift removal for improving the accuracy of gait parameters using wearable sensor systems.

Sensors (Basel) 2014 Dec 5;14(12):23230-47. Epub 2014 Dec 5.

Division of Human Mechanical Systems and Design, Faculty of Engineering, Hokkaido University, Sapporo 060-8628, Japan.

Accumulated signal noise will cause the integrated values to drift from the true value when measuring orientation angles of wearable sensors. This work proposes a novel method to reduce the effect of this drift to accurately measure human gait using wearable sensors. Firstly, an infinite impulse response (IIR) digital 4th order Butterworth filter was implemented to remove the noise from the raw gyro sensor data. Secondly, the mode value of the static state gyro sensor data was subtracted from the measured data to remove offset values. Thirdly, a robust double derivative and integration method was introduced to remove any remaining drift error from the data. Lastly, sensor attachment errors were minimized by establishing the gravitational acceleration vector from the acceleration data at standing upright and sitting posture. These improvements proposed allowed for removing the drift effect, and showed an average of 2.1°, 33.3°, 15.6° difference for the hip knee and ankle joint flexion/extension angle, when compared to without implementation. Kinematic and spatio-temporal gait parameters were also calculated from the heel-contact and toe-off timing of the foot. The data provided in this work showed potential of using wearable sensors in clinical evaluation of patients with gait-related diseases.
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http://dx.doi.org/10.3390/s141223230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299060PMC
December 2014

Three dimensional gait analysis using wearable acceleration and gyro sensors based on quaternion calculations.

Sensors (Basel) 2013 Jul 19;13(7):9321-43. Epub 2013 Jul 19.

Division of Human Mechanical Systems and Design, Faculty of Engineering, Hokkaido University, Sapporo, Japan.

This paper proposes a method for three dimensional gait analysis using wearable sensors and quaternion calculations. Seven sensor units consisting of a tri-axial acceleration and gyro sensors, were fixed to the lower limbs. The acceleration and angular velocity data of each sensor unit were measured during level walking. The initial orientations of the sensor units were estimated using acceleration data during upright standing position and the angular displacements were estimated afterwards using angular velocity data during gait. Here, an algorithm based on quaternion calculation was implemented for orientation estimation of the sensor units. The orientations of the sensor units were converted to the orientations of the body segments by a rotation matrix obtained from a calibration trial. Body segment orientations were then used for constructing a three dimensional wire frame animation of the volunteers during the gait. Gait analysis was conducted on five volunteers, and results were compared with those from a camera-based motion analysis system. Comparisons were made for the joint trajectory in the horizontal and sagittal plane. The average RMSE and correlation coefficient (CC) were 10.14 deg and 0.98, 7.88 deg and 0.97, 9.75 deg and 0.78 for the hip, knee and ankle flexion angles, respectively.
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http://dx.doi.org/10.3390/s130709321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3758651PMC
July 2013

Clinical usefulness of drug-eluting stents in the treatment of dialysis patients with coronary artery disease.

EuroIntervention 2011 Jan;6(6):754-9

Division of Cardiology, Cardiovascular Center, Akane Foundation Tsuchiya General Hospital, Hiroshima, Japan.

Aims: To investigate the clinical outcomes of paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES) in patients on dialysis.

Methods And Results: Between May 2004 and December 2008, 95 patients on dialysis with 124 lesions were treated with PES alone, and were compared to 184 patients on dialysis with 244 lesions treated with SES alone, retrospectively. One-year major adverse cardiac event (MACE) including stent thrombosis, target lesion revascularisation (TLR), myocardial infarction (MI) and cardiac death were compared. Baseline characteristics were similar except for previous CABG (p = 0.02) and reference vessel diameter (p = 0.04). During hospitalisation, all cause death was more frequently observed in the PES group (p = 0.004). In-hospital MACE was not significantly different (p = 0.8). The incidence of 1-year MACE in the PES group was lower than that in the SES group (14.7%, 28.3%, p = 0.04), mainly due to the reduction of TLR (11.6%, 25.0%, p = 0.03). Rates of stent thrombosis (0%, 2.7%, p = 0.1), MI (1.1%, 3.8%, p = 0.2), and cardiac death (3.2%, 4.4%, p = 0.6) were not significantly different.

Conclusions: PES appears to be more efficient in reducing angiographic and clinical restenosis in dialysis patients compared with SES.
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http://dx.doi.org/10.4244/EIJV6I6A128DOI Listing
January 2011

A case of acute coronary syndrome caused by extrinsic compression of the left main coronary artery due to pulmonary hypertension.

J Cardiol Cases 2010 Dec 3;2(3):e154-e158. Epub 2010 Aug 3.

Department of Cardiology, Cardiovascular Center, Tsuchiya General Hospital, 3-30 Nakajimacho Nakaku, Hiroshima City 730-8655, Japan.

Stenosis of the left main coronary artery (LMCA) due to extrinsic compression, producing symptoms of myocardial ischemia, is called left main compression syndrome. We report on a 43-year-old male with acute coronary syndrome who developed left main compression syndrome while waiting for a lung transplantation secondary to interstitial pneumonia, but underwent successful LMCA stenting as emergent treatment. Coronary angiography 3 months after the operation showed good stent patency in the LMCA, and the clinical course was favorable.
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http://dx.doi.org/10.1016/j.jccase.2010.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265230PMC
December 2010

Gait posture estimation using wearable acceleration and gyro sensors.

J Biomech 2009 Nov 13;42(15):2486-94. Epub 2009 Aug 13.

Division of Human Mechanical Systems and Design, Graduate School of Engineering, Hokkaido University, N13 W8, Kita-ku, Sapporo 060-8628, Japan.

A method for gait analysis using wearable acceleration sensors and gyro sensors is proposed in this work. The volunteers wore sensor units that included a tri-axis acceleration sensor and three single axis gyro sensors. The angular velocity data measured by the gyro sensors were used to estimate the translational acceleration in the gait analysis. The translational acceleration was then subtracted from the acceleration sensor measurements to obtain the gravitational acceleration, giving the orientation of the lower limb segments. Segment orientation along with body measurements were used to obtain the positions of hip, knee, and ankle joints to create stick figure models of the volunteers. This method can measure the three-dimensional positions of joint centers of the hip, knee, and ankle during movement. Experiments were carried out on the normal gait of three healthy volunteers. As a result, the flexion-extension (F-E) and the adduction-abduction (A-A) joint angles of the hips and the flexion-extension (F-E) joint angles of the knees were calculated and compared with a camera motion capture system. The correlation coefficients were above 0.88 for the hip F-E, higher than 0.72 for the hip A-A, better than 0.92 for the knee F-E. A moving stick figure model of each volunteer was created to visually confirm the walking posture. Further, the knee and ankle joint trajectories in the horizontal plane showed that the left and right legs were bilaterally symmetric.
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http://dx.doi.org/10.1016/j.jbiomech.2009.07.016DOI Listing
November 2009

Gait analysis using gravitational acceleration measured by wearable sensors.

J Biomech 2009 Feb 1;42(3):223-33. Epub 2009 Jan 1.

Division of Human Mechanical Systems and Design, Graduate School of Engineering, Hokkaido University, N13 W8, Kita-ku, Sapporo, Hokkaido 060-8628, Japan.

A novel method for measuring human gait posture using wearable sensor units is proposed. The sensor units consist of a tri-axial acceleration sensor and three gyro sensors aligned on three axes. The acceleration and angular velocity during walking were measured with seven sensor units worn on the abdomen and the lower limb segments (both thighs, shanks and feet). The three-dimensional positions of each joint are calculated from each segment length and joint angle. Joint angle can be estimated mechanically from the gravitational acceleration along the anterior axis of the segment. However, the acceleration data during walking includes three major components; translational acceleration, gravitational acceleration and external noise. Therefore, an optimization analysis was represented to separate only the gravitational acceleration from the acceleration data. Because the cyclic patterns of acceleration data can be found during constant walking, a FFT analysis was applied to obtain some characteristic frequencies in it. A pattern of gravitational acceleration was assumed using some parts of these characteristic frequencies. Every joint position was calculated from the pattern under the condition of physiological motion range of each joint. An optimized pattern of the gravitational acceleration was selected as a solution of an inverse problem. Gaits of three healthy volunteers were measured by walking for 20s on a flat floor. As a result, the acceleration data of every segment was measured simultaneously. The characteristic three-dimensional walking could be shown by the expression using a stick figure model. In addition, the trajectories of the knee joint in the horizontal plane could be checked by visual imaging on a PC. Therefore, this method provides important quantitive information for gait diagnosis.
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http://dx.doi.org/10.1016/j.jbiomech.2008.10.027DOI Listing
February 2009

Blockade of endogenous proinflammatory cytokines ameliorates endothelial dysfunction in obese Zucker rats.

Hypertens Res 2008 Apr;31(4):737-43

Department of Urology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

To study the role of endogenous proinflammatory cytokines in endothelial dysfunction in diabetes, we administered semapimod, an inhibitor of proinflammatory cytokine production, to obese Zucker (OZ) rats, and examined its effect on endothelium-dependent vasorelaxation. Endothelium-dependent vasorelaxation induced by acetylcholine and adrenomedullin (AM) was significantly reduced in OZ rats compared to a control group of lean Zucker rats. Semapimod significantly restored endothelium-dependent vasorelaxation in OZ rats. This effect of semapimod was well correlated with the reduction in the serum concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and C-reactive protein, as well as with the recovery of AM-induced Akt phosphorylation and cGMP production. Furthermore, acute administration of TNF-alpha significantly suppressed endothelium-dependent vasorelaxation and AM-induced cGMP production. These results implicate endogenous proinflammatory cytokines, especially TNF-alpha, in endothelial dysfunction in diabetes, and indicate that blockade of these cytokines will be a promising strategy for inhibiting the progression of vascular inflammation.
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http://dx.doi.org/10.1291/hypres.31.737DOI Listing
April 2008

Calcineurin is critical for sodium-induced neointimal formation in normotensive and hypertensive rats.

Am J Physiol Heart Circ Physiol 2008 Jun 2;294(6):H2871-8. Epub 2008 May 2.

Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

It is well known that excessive intake of sodium chloride (sodium) is a risk factor for cardiovascular disease because it raises blood pressure. However, sodium loading reportedly promotes cardiovascular disease independently of its effect on blood pressure. To examine the mechanisms by which sodium loading promotes vascular inflammation independently of its effect on blood pressure, we examined the role of calcineurin in sodium loading-induced vascular inflammation using a wire injury model of the rat femoral artery. Calcineurin mRNA expression in the wire-injured femoral artery was significantly higher in sodium-loaded normotensive rats, such as Wistar-Kyoto (WKY) rats, than that in control WKY rats. Neointimal formation was also significantly enhanced in sodium-loaded WKY rats compared with control WKY rats. Gene transfer of an adenovirus expressing a dominant negative mutant of calcineurin (AdCalADeltaC92Q) significantly suppressed neointimal formation in sodium-loaded WKY rats to a level similar to that observed in control WKY rats. Calcineurin expression and neointimal formation were more significantly enhanced in hypertensive rats, such as spontaneously hypertensive rats (SHRs), than those in control WKY rats. AdCalADeltaC92Q infection significantly suppressed neointimal formation in SHRs to a level similar to that observed in control WKY rats. These results suggest that sodium loading promotes neointimal formation, even in normotensive rats, and that hypertension further stimulates neointimal formation. These results also suggest that calcineurin plays a pivotal role in this process.
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http://dx.doi.org/10.1152/ajpheart.00031.2008DOI Listing
June 2008

Angiotensin II and tumor necrosis factor-alpha synergistically promote monocyte chemoattractant protein-1 expression: roles of NF-kappaB, p38, and reactive oxygen species.

Am J Physiol Heart Circ Physiol 2008 Jun 25;294(6):H2879-88. Epub 2008 Apr 25.

Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

We examined whether ANG II and TNF-alpha cooperatively induce vascular inflammation using the expression of monocyte chemoattractant protein (MCP)-1 as a marker of vascular inflammation. ANG II and TNF-alpha stimulated MCP-1 expression in a synergistic manner in vascular smooth muscle cells. ANG II-induced MCP-1 expression was potently inhibited to a nonstimulated basal level by blockade of the p38-dependent pathway but only partially inhibited by blockade of the NF-kappaB-dependent pathway. In contrast, TNF-alpha-induced MCP-1 expression was potently suppressed by blockade of NF-kappaB activation but only modestly suppressed by blockade of p38 activation. ANG II- and TNF-alpha-induced activation of NF-kappaB- and p38-dependent pathways was partially inhibited by pharmacological inhibitors of ROS production. Furthermore, ANG II- and TNF-alpha-stimulated MCP-1 expression was partially suppressed by ROS inhibitors. We also examined whether endogenous ANG II and TNF-alpha cooperatively promote vascular inflammation in vivo using a wire injury model of the rat femoral artery. Blockade of both ANG II and TNF-alpha further suppressed neointimal formation, macrophage infiltration, and MCP-1 expression in an additive manner compared with blockade of ANG II or TNF-alpha alone. These results suggested that ANG II and TNF-alpha synergistically stimulate MCP-1 expression via the utilization of distinct intracellular signaling pathways (p38- and NFkappaB-dependent pathways) and that these pathways are activated in ROS-dependent and -independent manners. These results also suggest that ANG II and TNF-alpha cooperatively stimulate vascular inflammation in vivo as well as in vitro.
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http://dx.doi.org/10.1152/ajpheart.91406.2007DOI Listing
June 2008

A Novel alpha1,2-L-fucosidase acting on xyloglucan oligosaccharides is associated with endo-beta-mannosidase.

J Biochem 2007 Dec 22;142(6):721-9. Epub 2007 Oct 22.

Department of Chemistry, Graduate School of Science, Osaka University, Osaka 560-0043, Japan.

Endo-beta-mannosidase, which hydrolyses the Manbeta1-4GlcNAc linkage of N-glycans in an endo-manner, was discovered in plants. During the course of the purification of the enzyme from lily flowers, we found a higher molecular mass form of the enzyme (designated as EBM II). EBM II was purified by column chromatography to homogeneity and its molecular composition revealed EBM II to be comprised of endo-beta-mannosidase and an associated protein. The cDNA of this associated protein encodes a protein with slight homology to the fucosidase domain of bifidus AfcA. EBM II has alpha1,2-L-fucosidase activity and acts on a fucosylated xyloglucan nonasaccharide. The amino acid sequence of this associated protein has no similarity to known plant alpha-L-fucosidases. These results show that EBM II is a novel alpha1,2-L-fucosidase and a protein complex containing endo-beta-mannosidase.
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http://dx.doi.org/10.1093/jb/mvm186DOI Listing
December 2007

High incidence of renal failure in patients with aortic aneurysms.

Nephrol Dial Transplant 2007 May 3;22(5):1361-8. Epub 2007 Feb 3.

Department of Nephrology, International Medical Center of Japan, 2-1-1 Hongo, Bunkyo-ku, 113-8421, Tokyo, Japan.

Background: Renal failure (RF) is a well-recognized complication of aortic aneurysms (AA) although its incidence has been poorly documented previously. The purpose of this study is to examine the incidence of RF in patients with AA and prognosis of AA patients with RF.

Methods: Renal function, complications and prognosis of AA patients with RF were retrospectively reviewed in 350 AA patients (median age 69.8+/-10.7 years) in the International Medical Center of Japan from 1989 to 1999.

Results: Among 350 patients with AA, 90 patients (25.7%) had chronic renal failure (CRF) at the initiation of follow-up. The number of CRF patients increased to 117 (33.4%) at 30 months of follow-up. Forty-four out of 160 patients (27.5%) who had aortic surgery developed postoperative acute renal failure (ARF). Stepwise logistic regression analysis revealed that age (>or=65 years), hypertension and multiple aneurysms were independent risk factors for CRF, whereas dissecting aneurysms, preoperative serum creatinine (sCr) levels and duration of surgery were independent risk factors for postoperative ARF in AA patients. In the 5-year follow-up of AA patients with CRF, the mean slopes of 1/serum-creatinine did not significantly differ between conservative treatment and surgical treatment. The survival rates were 49.5% in the conservative treatment group and 67.3% in the surgical treatment group.

Conclusion: Our data suggest that the management of renal function including blood pressure from an early stage in AA patients is important since CRF is highly prevalent in AA patients and affects their prognosis and mortality.
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http://dx.doi.org/10.1093/ndt/gfl779DOI Listing
May 2007

Effects of adrenomedullin on acute ischaemia-induced collateral development and mobilization of bone-marrow-derived cells.

Clin Sci (Lond) 2006 Dec;111(6):381-7

Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Adrenomedullin exerts not only vasodilatory effects, but also angiogenic effects. In the present study, we investigated the effects of adrenomedullin on collateral formation and circulating bone-marrow-derived cells after acute tissue ischaemia. Bone marrow of 8-10-week-old female C57BL/6J mice was replaced with that from GFP (green fluorescent protein) transgenic mice (GFP mice). At 8 weeks after transplantation, hindlimb ischaemia was induced by resecting the right femoral artery and a plasmid expressing human adrenomedullin (50 mug) was injected into the ischaemic muscle, followed by in vivo electroporation on a weekly basis. Overexpression of adrenomedullin significantly enhanced the blood flow recovery compared with controls (blood flow ratio, 1.0+/-0.2 compared with 0.6+/-0.3 respectively, at week 4; P<0.05) and increased capillary density in the ischaemic leg as determined by anti-CD31 immunostaining of the ischaemic muscle (567+/-40 compared with 338+/-65 capillaries/mm(2) respectively, at week 5; P<0.05). There were more GFP-positive cells in the thigh muscle of the mice injected with adrenomedullin than in that of the control mice (29.6+/-4.5 compared with 16.5+/-3.3 capillaries/mm(2) respectively, at week 5; P<0.05). We repeated the same experiments using LacZ-knock-in mice instead of GFP mice, and obtained similar results. These findings suggest that adrenomedullin may augment ischaemia-induced collateral formation with some effects on circulating bone-marrow-derived cells.
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http://dx.doi.org/10.1042/CS20060137DOI Listing
December 2006

Ghrelin improves renal function in mice with ischemic acute renal failure.

J Am Soc Nephrol 2006 Jan 23;17(1):113-21. Epub 2005 Nov 23.

Department of Cardiovascular Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Growth hormone and IGF-1 have been suggested to have tissue-protective effects. Ghrelin is a stomach-derived growth hormone secretagogue. The effects of ghrelin on ischemia/reperfusion-induced renal failure in mice were examined. Ischemic acute renal failure was induced by bilateral renal artery clamping for 45 min and reperfusion for 24 h. Ghrelin (100 microg/kg mouse) or vehicle was injected subcutaneously six times before surgery and three times after surgery every 8 h. Twenty-four hours after reperfusion, the right kidney was isolated and perfused. Acetylcholine (ACh)- and adrenomedullin-induced endothelium-dependent vasorelaxation of renal vessels significantly improved in ghrelin-pretreated mice (%Delta renal perfusion pressure by 10(-7) M ACh -63.5 +/- 3.7 versus -41.2 +/- 5.5%; P < 0.05). This change was associated with significant increases of nitric oxide release in the kidneys of ghrelin-treated mice (10(-7) M ACh 35.5 +/- 5.8 versus 16.9 +/- 3.5 fmol/g kidney per min; P < 0.05). Serum concentration of urea nitrogen (53 +/- 7 versus 87 +/- 15 mg/dl; P < 0.05) and renal injury score were significantly lower in the ghrelin group (2.5 +/- 0.8 versus 5.3 +/- 1.5; P < 0.01). Tubular apoptotic index was significantly lower in the ghrelin group (5 +/- 5 versus 28 +/- 4; P < 0.05). Furthermore, the survival rate after the 60-min ischemic period was higher in the ghrelin group (80 versus 20%; P < 0.05). Ghrelin treatment significantly increased the serum level of IGF-1. However, such renal protective effects of ghrelin on ischemia/reperfusion injury were not observed in insulin receptor substrate-2 knockout mice. These results suggest that ghrelin may protect the kidneys from ischemia/reperfusion injury and that this effect is related to an improvement of endothelial function through an IGF-1-mediated pathway.
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http://dx.doi.org/10.1681/ASN.2004080626DOI Listing
January 2006

Long-term effect of imidapril hydrochloride compared with dilazep hydrochloride administration on blood pressure and renal function in patients with chronic glomerulonephritis.

Int Heart J 2005 Jul;46(4):701-10

Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

The objective of the present study was to compare the effects of imidapril hydrochloride, an angiotensin converting enzyme inhibitor, and dilazep hydrochloride, an antiplatelet agent, on urinary protein excretion and renal function in patients with chronic glomerulonephritis. Imidapril (2.5 or 5 mg/day) or dilazep (300 or 450 mg/day) was administered for 3 years. Blood pressure, proteinuria, and renal function were measured before and during the treatment. In the group administered imidapril (n = 11), urinary protein decreased by approximately 50% (2.16 +/- 1.57 versus 0.90 +/- 0.53 g/g Cr, P < 0.01) and blood pressure by 14/10 mmHg (139.6 +/- 17.4/93.6 +/- 8.7 mmHg versus 122.7 +/- 10.5/81.8 +/- 9.9 mmHg, P < 0.01) and both remained at low levels during the three years of treatment. No correlation was observed between the extent of blood pressure reduction and changes in urinary protein. Serum creatinine concentrations did not change significantly (1.3 +/- 0.3 versus 1.3 +/- 0.3 mg/dL, NS). In the dilazep group (n = 12), there were no significant changes in blood pressure, urinary protein, or serum creatinine. These findings demonstrate that imidapril reduces proteinuria and contributes to preserve renal function, suggesting its usefulness in the treatment of patients with chronic glomerulonephritis.
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http://dx.doi.org/10.1536/ihj.46.701DOI Listing
July 2005

Blockade of endogenous cytokines mitigates neointimal formation in obese Zucker rats.

Circulation 2005 Mar;111(11):1398-406

Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

Background: It is well known that diabetes mellitus is a major risk factor for vascular diseases such as atherosclerosis and restenosis after angioplasty. It has become clear that advanced glycation end products (AGE) and their receptor (RAGE) are implicated in vascular diseases, especially in diabetes mellitus. Nevertheless, the mechanisms by which diabetes mellitus is often associated with vascular diseases remain unclear.

Methods And Results: To study the role of endogenous cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 in the development of vascular diseases and in the expression of RAGE, we used semapimod, a pharmacological inhibitor of cytokine production, and examined its effect on neointimal formation in the femoral artery of obese Zucker (OZ) rats. We also used an adenovirus construct expressing a dominant negative mutant of the receptor for TNF-alpha (AdTNFRDeltaC) to block the action of endogenous TNF-alpha. Semapimod significantly suppressed neointimal formation and RAGE expression in OZ rats compared with untreated OZ rats. This inhibitory effect of semapimod on neointimal formation was overcome by infection of an adenovirus expressing RAGE into the femoral artery of OZ rats. Furthermore, AdTNFRDeltaC infection significantly suppressed neointimal formation and RAGE expression in the femoral artery of OZ rats.

Conclusions: These results suggest that endogenous cytokines, especially TNF-alpha, were implicated in neointimal formation in OZ rats and that RAGE was a mediator of the effect of these cytokines on neointimal formation.
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http://dx.doi.org/10.1161/01.CIR.0000158482.83179.DBDOI Listing
March 2005

Endothelial dysfunction and hypercontractility of vascular myocytes are ameliorated by fluvastatin in obese Zucker rats.

Am J Physiol Heart Circ Physiol 2005 Apr 18;288(4):H1770-6. Epub 2004 Nov 18.

Department of Urology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 Japan.

To study the mechanisms of vascular dysfunction in diabetes mellitus, we examined the responses of the aorta to adrenomedullin (AM) and ANG II in obese Zucker (OZ), lean Zucker (LZ), and OZ rats administered fluvastatin (OZ + Flu). AM-induced endothelium-dependent vasorelaxation was impaired in OZ rats compared with LZ rats, and fluvastatin restored AM-induced, endothelium-dependent vasorelaxation (%Deltatension at 10(-7) mol/l AM; LZ, -85.1 +/- 3.1%; OZ, -50.7 +/- 2.5%; OZ + Flu, -75.6 +/- 2.7%). Expression of endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in response to AM (10(-7) mol/l) were also diminished in OZ rats. Fluvastatin restored the eNOS expression and Akt phosphorylation [eNOS expression (relative intensity): LZ, 2.3 +/- 0.4; OZ, 1.0 +/- 0.2; OZ + Flu, 1.8 +/- 0.3; Akt phosphorylation (relative intensity): LZ, 2.3 +/- 0.2; OZ, 1.0 +/- 0.3; OZ + Flu, 1.9 +/- 0.2]. ANG II-induced vasoconstriction was enhanced in the aortic rings of OZ rats compared with LZ rats, and this enhanced vasoconstriction was partially normalized by fluvastatin and was abolished when the aorta of OZ rats was preincubated with the Rho kinase inhibitor Y-27632. GTPgammaS-induced contraction of permeabilized aortic smooth muscle cells, which is an indicator of the Rho-dependent Ca(2+) sensitization of contraction, was enhanced in OZ rats compared with LZ rats, and this enhanced contraction was suppressed in OZ + Flu rats. These results suggested that endothelium-dependent vasorelaxation was impaired, Ca(2+) sensitization of contraction was augmented in blood vessels of OZ rats and that fluvastatin restored vascular function by activating the Akt-dependent pathway and inhibiting the Rho-dependent pathway.
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http://dx.doi.org/10.1152/ajpheart.00751.2004DOI Listing
April 2005

AMP-activated protein kinase inhibits angiotensin II-stimulated vascular smooth muscle cell proliferation.

Circulation 2004 Jul 19;110(4):444-51. Epub 2004 Jul 19.

Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Background: AMP-activated protein kinase (AMPK) is a stress-activated protein kinase that works as a metabolic sensor of cellular ATP levels. Here, we investigated whether AMPK signaling has a role in the regulation of the angiotensin II (Ang II)-induced proliferation signal in rat vascular smooth muscle cells (VSMCs).

Methods And Results: Aminoimidazole-4-carboxamide-1-beta-ribofuranoside (AICAR) activated AMPK in rat VSMCs and inhibited Ang II-induced extracellular signal-regulated kinase 1/2 phosphorylation but not that of p38 MAPK or Akt/PKB. Although Ang II activated AMPK, this activation was significantly inhibited by catalase, N-acetylcysteine, and diphenyleneiodonium chloride, an NADPH oxidase inhibitor. Moreover, the observation that AMPK was activated by H2O2 suggests that AMPK is redox sensitive. The Ang II type 1 receptor antagonist valsartan but not the Ang II type 2 receptor antagonist PD123319 significantly inhibited Ang II-induced AMPK activation, suggesting that Ang II-induced AMPK activation was Ang II type 1 receptor dependent. Whereas 3H-thymidine incorporation by VSMCs treated with Ang II was significantly inhibited when the cells were pretreated with 1 mmol/L AICAR, the inhibition of AMPK by dominant-negative AMPK overexpression augmented Ang II-induced cell proliferation. Subcutaneous injection of AICAR (1 mg/g body weight per day) for 2 weeks suppressed neointimal formation after transluminal mechanical injury of the rat femoral artery.

Conclusions: Our findings indicate that Ang II-induced AMPK activation is synchronized with extracellular signal-regulated kinase signaling and that AMPK works as an inhibitor of the Ang II proliferative pathway. AMPK signaling might serve as a new therapeutic target of vascular remodeling in cardiovascular diseases.
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http://dx.doi.org/10.1161/01.CIR.0000136025.96811.76DOI Listing
July 2004

Myocyte enhancer factor 2 mediates vascular inflammation via the p38-dependent pathway.

Circ Res 2004 Jul 3;95(1):42-9. Epub 2004 Jun 3.

Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Although it has been established that myocyte enhancer factor 2 (MEF2) plays pivotal roles in the development of the cardiovascular system as well as skeletal muscle cells, little is known of its role in vascular inflammatory diseases such as atherosclerosis and restenosis after angioplasty. To investigate the role of MEF2 in vascular inflammation and that of p38 in the activation of MEF2, we infected cultured rat vascular smooth muscle cells (VSMCs) with an adenovirus construct expressing a dominant-negative mutant of MEF2A (MEF2ASA) or mitogen-activated protein kinase kinase 6 (MEK6AA), and examined their effects on the expression of monocyte chemoattractant protein-1 (MCP-1), which is known to play important roles in vascular inflammation. We also examined the role of MEF2 in vivo using a rat model of transluminal wire-induced injury of the femoral artery. Angiotensin II (Ang II)-induced expression of MCP-1 mRNA was significantly inhibited by infection with adenoviruses encoding MEF2ASA (AdMEF2ASA) or MEK6AA. Ang II-induced increase of MCP-1 promoter activity was also significantly suppressed by overexpression of MEF2ASA or MEK6AA. Ang II stimulated the transactivating function of MEF2A and this activation was inhibited by overexpression of MEK6AA. Infection with AdMEF2ASA suppressed MCP-1 expression in the femoral artery after the transluminal mechanical injury. AdMEF2ASA infection also inhibited macrophages infiltration and neointimal formation in the wire-injured femoral arteries. These results suggested that MEF2 activation via the p38-dependent pathway mediates vascular inflammation via stimulation of MCP-1 expression in VSMCs and macrophages infiltration.
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http://dx.doi.org/10.1161/01.RES.0000134631.75684.4ADOI Listing
July 2004

Calcineurin promotes the expression of monocyte chemoattractant protein-1 in vascular myocytes and mediates vascular inflammation.

Circ Res 2004 Mar 22;94(5):693-700. Epub 2004 Jan 22.

Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.

Although the role of the calcineurin-dependent pathway in the development of cardiac hypertrophy has been intensively studied, little is known of its role in vascular inflammatory diseases such as atherosclerosis and restenosis after angioplasty. To help elucidate the role of calcineurin in vascular inflammation, we infected cultured vascular smooth muscle cells (VSMCs) with an adenovirus construct expressing a constitutively active mutant of calcineurin, and examined its effect on the expression of monocyte chemoattractant protein-1 (MCP-1). We also examined the role of calcineurin in vivo using a transluminal wire injury model of the rat femoral artery. Forced activation of calcineurin significantly increased the expression of MCP-1 both at the transcriptional and protein levels. Angiotensin II (Ang II) also significantly stimulated MCP-1 expression, and this increase was significantly inhibited by cyclosporin A (CyA). Constitutive activation of calcineurin stabilized MCP-1 mRNA without enhancing MCP-1 promoter activity. In accordance with the results, Ang II-induced increase of MCP-1 promoter activity was not suppressed by CyA. Ang II stabilized MCP-1 mRNA, and this effect of Ang II was diminished by CyA. CyA suppressed MCP-1 expression in the femoral artery after the transluminal mechanical injury. CyA also inhibited macrophage infiltration and neointimal formation in the wire-injured femoral arteries. These results suggested that calcineurin mediates vascular inflammation via stimulation of MCP-1 expression in VSMCs and macrophage infiltration.
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http://dx.doi.org/10.1161/01.RES.0000118250.67032.5EDOI Listing
March 2004

Endothelial responses of the aorta from adrenomedullin transgenic mice and knockout mice.

Hypertens Res 2003 Feb;26 Suppl:S79-84

Department of Urology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Adrenomedullin (AM) is a potent vascular wall-derived vasorelaxing peptide which induces the release of nitric oxide (NO). To explore the role of endogenous AM in vascular function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists [AM (22-52), and calcitonin gene-related peptide (CGRP) (8-37)] on the isometric tension of aortic rings isolated from AM transgenic (TG) and knockout (KO) mice and wild type littermates (WT). ACh and AM caused a dose-dependent reduction of the isometric tension of aortic rings, but the degree of vasodilatation was smaller in TG than in KO or WT (% delta tension [10(-6) mol/l ACh]: KO -69 +/- 10%, WT -39 +/- 8%, TG -29 +/- 1%, p < 0.01). On the other hand, N(G)-nitro-L-arginine methyl ester, an NO synthase inhibitor, induced greater vasoconstriction in TG (% delta tension 10(-5)mol/l: KO +78 +/- 16%, WT +99 +/- 27%, TG +184 +/- 20%, p < 0.01), whereas E-4021, a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase inhibitor, caused greater vasodilation in TG mice. Both AM antagonists increased tension in TG to a greater extent than in KO or WT mice (% delta tension [10(-6) mol/l CGRP (8-37)]: KO +24 +/- 5%, WT +51 +/- 6%, TG +75 +/- 7%, p < 0.01). Endothelial denudation of the aorta diminished the vasoconstriction caused by the AM antagonists. In conclusion, the amounts of AM expressed in the aortic endothelium influenced baseline NO release. AM antagonists increased vascular tone in WT as well as in TG, suggesting that endogenous AM plays a physiological role in the regulation of aortic tone.
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http://dx.doi.org/10.1291/hypres.26.s79DOI Listing
February 2003
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