Updated on 2024/12/18

写真a

 
KAIHARA KEIKO
 
Organization
Department of Comprehensive Technical Solutions Technical Expert staff
Position
Technical Expert staff
External link

Research Interests

  • 生理学

  • 生体医工学

Research Areas

  • Life Science / Physiology

 

Papers

  • Direct Binding of Synaptopodin 2-Like Protein to Alpha-Actinin Contributes to Actin Bundle Formation in Cardiomyocytes Reviewed

    Hiroshi Yamada, Hirona Osaka, Nanami Tatsumi, Miu Araki, Tadashi Abe, Keiko Kaihara, Ken Takahashi, Eizo Takashima, Takayuki Uchihashi, Keiji Naruse, Kohji Takei

    Cells   13 ( 16 )   1373 - 1373   2024.8

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    Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

    Synaptopodin 2-like protein (SYNPO2L) is localized in the sarcomere of cardiomyocytes and is involved in heart morphogenesis. However, the molecular function of SYNPO2L in the heart is not fully understood. We investigated the interaction of SYNPO2L with sarcomeric α-actinin and actin filaments in cultured mouse cardiomyocytes. Immunofluorescence studies showed that SYNPO2L colocalized with α-actinin and actin filaments at the Z-discs of the sarcomere. Recombinant SYNPO2La or SYNPO2Lb caused a bundling of the actin filaments in the absence of α-actinin and enhanced the α-actinin-dependent formation of actin bundles. In addition, high-speed atomic force microscopy revealed that SYNPO2La directly bound to α-actinin via its globular ends. The interaction between α-actinin and SYNPO2La fixed the movements of the two proteins on the actin filaments. These results strongly suggest that SYNPO2L cooperates with α-actinin during actin bundle formation to facilitate sarcomere formation and maintenance.

    DOI： 10.3390/cells13161373

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  • Stretch‐induced reactive oxygen species contribute to the Frank–Starling mechanism Reviewed

    Keiko Kaihara, Hiroaki Kai, Yumiko Chiba, Keiji Naruse, Gentaro Iribe

    The Journal of Physiology   2023.4

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    Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    DOI： 10.1113/jp284283

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  • High hydrostatic pressure induces slow contraction in mouse cardiomyocytes Reviewed

    Yamaguchi Y, Nishiyama M, Kai H, Kaneko T, Kaihara K, Iribe G, Takai A, Naruse K, Morimatsu M

    Biophysical Journal   122 ( 1 )   267 - 267   2023.1

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.bpj.2022.11.2940

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  • High hydrostatic pressure induces slow contraction in mouse cardiomyocytes. International journal

    Yohei Yamaguchi, Masayoshi Nishiyama, Hiroaki Kai, Toshiyuki Kaneko, Keiko Kaihara, Gentaro Iribe, Akira Takai, Keiji Naruse, Masatoshi Morimatsu

    Biophysical journal   62 ( Supplement 1-2 )   2022.7

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    Language：English  

    Cardiomyocytes are contractile cells that regulate heart contraction. Ca2+ flux via Ca2+ channels activates actomyosin interactions, leading to cardiomyocyte contraction, which is modulated by physical factors (e.g., stretch, shear stress, and hydrostatic pressure). We evaluated the mechanism triggering slow contractions using a high-pressure microscope to characterize changes in cell morphology and intracellular Ca2+ concentration ([Ca2+]i) in mouse cardiomyocytes exposed to high hydrostatic pressures. We found that cardiomyocytes contracted slowly without an acute transient increase in [Ca2+]i, while a myosin ATPase inhibitor interrupted pressure-induced slow contractions. Furthermore, transmission electron microscopy showed that, although the sarcomere length was shortened upon the application of 20 MPa, this pressure did not collapse cellular structures such as the sarcolemma and sarcomeres. Our results suggest that pressure-induced slow contractions in cardiomyocytes are driven by the activation of actomyosin interactions without an acute transient increase in [Ca2+]i.

    DOI： 10.1016/j.bpj.2022.07.016

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  • Ischemia Enhances the Acute Stretch-Induced Increase in Calcium Spark Rate in Ventricular Myocytes

    Breanne A. Cameron, Hiroaki Kai, Keiko Kaihara, Gentaro Iribe, T. Alexander Quinn

    Frontiers in Physiology   11   2020.4

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media S.A.  

    Introduction: In ventricular myocytes, spontaneous release of calcium (Ca2+) from the sarcoplasmic reticulum via ryanodine receptors (“Ca2+ sparks”) is acutely increased by stretch, due to a stretch-induced increase of reactive oxygen species (ROS). In acute regional ischemia there is stretch of ischemic tissue, along with an increase in Ca2+ spark rate and ROS production, each of which has been implicated in arrhythmogenesis. Yet, whether there is an impact of ischemia on the stretch-induced increase in Ca2+ sparks and ROS has not been investigated. We hypothesized that ischemia would enhance the increase of Ca2+ sparks and ROS that occurs with stretch. Methods: Isolated ventricular myocytes from mice (male, C57BL/6J) were loaded with fluorescent dye to detect Ca2+ sparks (4.6 μM Fluo-4, 10 min) or ROS (1 μM DCF, 20 min), exposed to normal Tyrode (NT) or simulated ischemia (SI) solution (hyperkalemia [15 mM potassium], acidosis [6.5 pH], and metabolic inhibition [1 mM sodium cyanide, 20 mM 2-deoxyglucose]), and subjected to sustained stretch by the carbon fiber technique (~10% increase in sarcomere length, 15 s). Ca2+ spark rate and rate of ROS production were measured by confocal microscopy. Results: Baseline Ca2+ spark rate was greater in SI (2.54 ± 0.11 sparks·s−1·100 μm−2
    n = 103 cells, N = 10 mice) than NT (0.29 ± 0.05 sparks·s−1·100 μm−2
    n = 33 cells, N = 9 mice
    p &lt
    0.0001). Stretch resulted in an acute increase in Ca2+ spark rate in both SI (3.03 ± 0.13 sparks·s−1·100 μm−2
    p &lt
    0.0001) and NT (0.49 ± 0.07 sparks·s−1·100 μm−2
    p &lt
    0.0001), with the increase in SI being greater than NT (+0.49 ± 0.04 vs. +0.20 ± 0.04 sparks·s−1·100 μm−2
    p &lt
    0.0001). Baseline rate of ROS production was also greater in SI (1.01 ± 0.01 normalized slope
    n = 11, N = 8 mice) than NT (0.98 ± 0.01 normalized slope
    n = 12, N = 4 mice
    p &lt
    0.05), but there was an acute increase with stretch only in SI (+12.5 ± 2.6%
    p &lt
    0.001). Conclusion: Ischemia enhances the stretch-induced increase of Ca2+ sparks in ventricular myocytes, with an associated enhancement of stretch-induced ROS production. This effect may be important for premature excitation and/or in the development of an arrhythmogenic substrate in acute regional ischemia.

    DOI： 10.3389/fphys.2020.00289

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  • L-type calcium channel modulates mechanosensitivity of the cardiomyocyte cell line H9c2. Reviewed International journal

    Ken Takahashi, Shogo Hayashi, Mari Miyajima, Marei Omori, Jing Wang, Keiko Kaihara, Masatoshi Morimatsu, Chen Wang, Jian Chen, Gentaro Iribe, Keiji Naruse, Masahiro Sokabe

    Cell calcium   79   68 - 74   2019.5

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    Language：English   Publishing type：Research paper (scientific journal)  

    The application of mechanical stimuli to cells often induce increases in intracellular calcium, affecting the regulation of a variety of cell functions. Although the mechanism of mechanotransduction-induced calcium increases has not been fully resolved, the involvement of mechanosensitive ion channels in the plasma membrane and the endoplasmic reticulum has been reported. Here, we demonstrate that voltage-gated L-type calcium channels play a critical role in the mechanosensitive calcium response in H9c2 rat cardiomyocytes. The intracellular calcium level in H9c2 cells increased in a reproducible dose-dependent manner in response to uniaxial stretching. The stretch-activated calcium response (SICR) completely disappeared in calcium-free medium, whereas thapsigargin and cyclopiazonic acid, inhibitors of sarcoendoplasmic reticulum calcium ATPase, partially reduced the SICR. These findings suggest that both calcium influx across the cell membrane and calcium release from the sarcoendoplasmic reticulum are involved in the SICR. Nifedipine, diltiazem, and verapamil, inhibitors of L-type calcium channels, reduced the SICR in a dose-dependent manner. Furthermore, small interfering RNA against the L-type calcium channel α1c subunit diminished the SICR dramatically. Nifedipine also diminished the mechanosensitivity of Langendorff-perfused rat heart. These results suggest that the SICR in H9c2 cardiomyocytes involves the activation of L-type calcium channels and subsequent calcium release from the sarcoendoplasmic reticulum.

    DOI： 10.1016/j.ceca.2019.02.008

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  • Mechano-sensitivity of mitochondrial function in mouse cardiac myocytes Reviewed

    Gentaro Iribe, Keiko Kaihara, Yohei Yamaguchi, Michio Nakaya, Ryuji Inoue, Keiji Naruse

    Progress in Biophysics and Molecular Biology   130 ( Pt B )   315 - 322   2017.11

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

    Mitochondria are an important source of reactive oxygen species (ROS). Although it has been reported that myocardial stretch increases cellular ROS production by activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), referred to as X-ROS signalling, the involvement of mitochondria in X-ROS is not clear. Mitochondria are organelles that generate adenosine triphosphate (ATP) for cellular energy needs, which are mechanical-load-dependent. Therefore, it would not be surprising if these organelles had mechano-sensitive functions associated with stretch-induced ROS production. In the present study, we investigated the relation between X-ROS and mitochondrial stretch-sensitive responses in isolated mouse cardiac myocytes. The cells were subjected to 10% axial stretch using computer-controlled, piezo-manipulated carbon fibres attached to both cell ends. Cellular ROS production and mitochondrial membrane potential (Δψm) were assessed optically by confocal microscopy. The axial stretch increased ROS production and hyperpolarised Δψm. Treatment with a mitochondrial metabolic uncoupler, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), at 0.5 μM did not suppress stretch-induced ROS production, whereas treatment with a respiratory Complex III inhibitor, antimycin A (5 μM), blunted the response. Although NOX inhibition by apocynin abrogated the stretch-induced ROS production, it did not suppress stretch-induced hyperpolarisation of Δψm. These results suggest that stretch causes activation of the respiratory chain to hyperpolarise Δψm, followed by NOX activation, which increases ROS production.

    DOI： 10.1016/j.pbiomolbio.2017.05.015

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  • Effects of axial stretch on mitochondrial reactive oxygen species in cardiac myocytes Reviewed

    Gentaro Iribe, Keiko Kaihara, Keiji Naruse

    Transactions of Japanese Society for Medical and Biological Engineering   52   44   2014.8

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    Language：English   Publisher：Japan Soc. of Med. Electronics and Biol. Engineering  

    Myocardium contracts against ventricular wall stretch that comes along with ventricular filling. Mitochondria generate required ATP for myocardial contraction. It is well known that mitochondrial ATP production process is one of the sources of reactive oxygen species (ROS). ROS are known as toxic molecules, but also important physiological regulators of intracellular signaling pathways. In the present study, we investigate the relation between myocardial stretch and mitochondrial ROS production, and discuss the role of mitochondria on myocardial response to stretch. Isolated mouse ventricular myocytes were exposed to 10% axial stretch using carbon fiber technique. ROS production was studied using DCF-loaded cells. Axial stretch significantly increased ROS production. Applying 5 μM mitochondrial metabolic uncoupler FCCP blunted the response, indicating mitochondrial ROS production is stretch-sensitive. The present results suggest that stretch enhances electron transport chain to prepare for the more ATP production for the more preloaded, namely, the more energy-consuming contraction.

    DOI： 10.11239/jsmbe.52.SY-44

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  • Effect of azelnidipine and amlodipine on single cell mechanics in mouse cardiomyocytes Reviewed

    Gentaro Iribe, Keiko Kaihara, Hiroshi Ito, Keiji Naruse

    EUROPEAN JOURNAL OF PHARMACOLOGY   715 ( 1-3 )   142 - 146   2013.9

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

    Azelnidipine and amlodipine are dihydropyridine-type Ca2+ channel blockers for the treatment of hypertension. Although these drugs have high vasoselectivity and small negative inotropic effects in vivo, little is known regarding their direct effects on cellular contractility without humoral regulation or the additive effects of these drugs with other antihypertensive drugs on myocardial contractility. To investigate the effects of Ca2+ channel blockers on single cell mechanics, mouse cardiomyocytes were enzymatically isolated, and a pair of carbon fibers was attached to opposite cell-ends to stretch the cells. Cells were paced at 4 Hz superfused in normal Tyrode solution at 37 C. Cell length and active/passive force calculated from carbon fiber bending were recorded in 6 different preload conditions. Slopes of end-systolic force length relation curves (maximum elastance) were measured as an index of contractility before and after drugs were administered. Azelniclipine at 10 nM and 100 nM did not change maximum elastance, while amlodipine at 100 nM did decrease maximum elastance. The combination of RNH-6270 (active form of angiotensin II receptor blocker, olmesartan, 10 nM) and either amlodipine (10 nM) or azelnidipine (10 nM) did not affect maximum elastance. Although both amlodipine and azelnidipine can be used safely at therapeutically relevant concentrations even in combination with olmesartan, the present results suggest that azelnidipine has a less negative inotropic action compared to amlodipine. (C) 2013 Elsevier B.V. All rights reserved,

    DOI： 10.1016/j.ejphar.2013.05.030

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  • Improvement in Carbon Fiber Technique for Cardiomyocyte Mechanics and Mechano-Electric Coupling Study

    Iribe Gentaro, Kaneko Toshiyuki, Yamaguchi Yohei, Kaihara Keiko, Naruse Keiji

    BME   51   M - 32-M-32   2013

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    Language：English   Publisher：Japanese Society for Medical and Biological Engineering  

    DOI： 10.11239/jsmbe.51.M-32

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  • The mechanical stimulation of cells in 3D culture within a self-assembling peptide hydrogel Reviewed

    Yusuke Nagai, Hidenori Yokoi, Keiko Kaihara, Keiji Naruse

    BIOMATERIALS   33 ( 4 )   1044 - 1051   2012.2

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

    The aim of this present study was to provide a scaffold as a tool for the investigation of the effect of mechanical stimulation on three-dimensionally cultured cells. For this purpose, we developed an artificial self-assembling peptide (SPG-178) hydrogel scaffold. The structural properties of the SPG-178 peptide were confirmed by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and transmission electron microscopy (TEM). The mechanical properties of the SPG-178 hydrogel were studied using rheology measurements. The SPG-178 peptide was able to form a stable, transparent hydrogel in a neutral pH environment In the SPG-178 hydrogel, mouse skeletal muscle cells proliferated successfully (increased by 12.4 +/- 1.5 times during 8 days of incubation; mean +/- SEM). When the scaffold was statically stretched, a rapid phosphorylation of ERK was observed (increased by 2.8 +/- 0.2 times; mean +/- SEM). These results demonstrated that the developed self-assembling peptide gel is non-cytotoxic and is a suitable tool for the investigation of the effect of mechanical stimulation on three-dimensional cell culture. (C) 2011 Elsevier Ltd. All rights reserved.

    DOI： 10.1016/j.biomaterials.2011.10.049

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  • Effects of axial stretch on sarcolemmal BKCa channels in post-hatch chick ventricular myocytes Reviewed

    Gentaro Iribe, Honghua Jin, Keiko Kaihara, Keiji Naruse

    EXPERIMENTAL PHYSIOLOGY   95 ( 6 )   699 - 711   2010.6

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

    We have previously reported the electrophysiological properties of sarcolemmal stretch-activated BKCa (SAKCA) channels cloned from cultured chick embryonic ventricular myocytes. However, the role of BKCa channels in the electrophysiology of the more mature heart is not clear. We have investigated the effects on the BKCa current of axial stretch in post-hatch ventricular myocytes. Whole-cell currents of ventricular myocytes isolated from 2-week-old chicks were recorded using the patch-clamp technique, while the cells were either held at resting length or stretched to cause a 10% increase in sarcomere length using a pair of carbon fibres attached to opposite ends of the cell. Stretch did not affect whole-cell currents immediately after the stretch was applied. However, sustained stretch for 3 min significantly increased outward currents. This stretch-induced change was reversed by applying 10 nm iberiotoxin, a specific BKCa channel blocker, or a Na+-Ca2+-free environment. These results were reproduced in a computer simulation study. The present study is the first report about the sarcolemmal BKCa current from post-hatch ventricular myocytes. The present results suggest that axial stretch activates BKCa channels via a stretch-induced increase in the cytosolic Na+ concentration followed by an increased Ca2+ influx.

    DOI： 10.1113/expphysiol.2009.051896

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  • Antigenic structures recognized by anti-beta 2-glycoprotein I auto-antibodies Reviewed

    H Kasahara, E Matsuura, K Kaihara, D Yamamoto, K Kobayashi, J Inagaki, K Ichikawa, A Tsutsumi, S Yasuda, T Atsumi, T Yasuda, T Koike

    INTERNATIONAL IMMUNOLOGY   17 ( 12 )   1533 - 1542   2005.12

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

    beta 2-Glycoprotein I (beta 2-GPI) is a major antigen for anti-cardiolipin antibodies and their epitopes are cryptic. Conformation of each domain of beta 2-GPI was optimized from its crystal structure by energy minimization and by molecular dynamics simulation. Three electrostatic interactions, i.e. D-193-K-246, D-222-K-317 and E-228-K-308, were observed between domains IV and V in the optimized structure that was constructed based on the consensus sequences obtained by the phage-displayed random peptide library. Antigenic structures determined by the epitope mapping mainly consisted of hydrophobic amino acids located on two discontinuous sequences in domain IV. These amino acid clusters, as an epitope, were covered by domain V and were of a hidden nature. A similar but incomplete counterpart to the epitopic clusters was found in domain I but was not in domains II or III. Binding of anti-beta 2-GPI auto-antibodies to solid-phase beta 2-GPI was significantly reduced either by L replacement for W-235, a common amino acid component for the epitopes, or by V replacement for all of D-193, D-222 and E-228. Structural analysis indicated a hypothesis that these electrostatic interactions between domains IV and V retained exposure to W-235 and that epitope spreading occurred in the region surrounding W-235. Thus, epitopic structures recognized by anti-beta 2-GPI auto-antibodies are cryptic and inter-domain electrostatic interactions are involved in their in exposure.

    DOI： 10.1093/intimm/dxh330

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  • Significance of valine/leucine(247) polymorphism of beta(2)-glycoprotein I in antiphospholipid syndrome - Increased reactivity of anti-beta(2)-glycoprotein I autoantibodies to the valine(247) gamma(2)-glycoprotein I variant Reviewed

    S Yasuda, T Atsumi, E Matsuura, K Kaihara, D Yamamoto, K Ichikawa, T Koike

    ARTHRITIS AND RHEUMATISM   52 ( 1 )   212 - 218   2005.1

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

    Objective. To clarify the consequences of the valise/leucine polymorphism at position 247 of the beta(2)-glycoprotein I (beta(2)GPI) gene in patients with antiphospholipid syndrome (APS), by investigating the correlation between genotypes and the presence of anti-beta(2)GPI antibody. The reactivity of anti-beta(2)GPI antibodies was characterized using recombinant Val(247) and Leu(247) beta(2)GPI.
    Methods. Sixty-five Japanese patients with APS and/or systemic lupus erythematosus who were positive for antiphospholipid antibodies and 61 controls were analyzed for the presence of the Val/Leu(247) polymorphism of beta(2)GPI. Polymorphism assignment was determined by polymerase chain reaction followed by restriction enzyme digestion. Recombinant Val(247) and Leu(247) beta(2)GPI were established to compare the reactivity of anti-beta(2)GPI antibodies to beta(2)GPI between these variants. The variants were prepared on polyoxygenated plates or cardiolipin-coated plates, and the reactivity of a series of anti-beta(2)GPI antibodies (immunized anti-human beta(2)GPI monoclonal antibodies [Cof-19-21] and autoimmune anti-beta(2)GPI monoclonal antibodies [EYIC8, EY2C9, and TMIG2]) and IgGs purified from patient sera was investigated.
    Results. A positive correlation between the Val(247) allele and the presence of anti-beta(2)GPI antibodies was observed in the patient group. Human monoclonal/polyclonal anti-beta(2)GPI autoantibodies showed higher binding to recombinant Val(247) beta(2)GPI than to Leu(247) beta(2)GPI, although no difference in the reactivity of the immunized anti-beta(2)GPI between these variants was observed. Conformational optimization showed that the replacement of Leu(247) by Val(247) led to a significant alteration in the tertiary structure of domain V and/or the domain IV-V interaction. Conclusion. The Val(247) beta(2)GPI allele was associated with both a high frequency of anti-beta(2)GPI antibodies and stronger reactivity with anti-beta(2)GPI antibodies compared with the Leu(247) beta(2)GPI allele, suggesting that the Val(247) beta(2)GPI allele may be one of the genetic risk factors for development of APS.

    DOI： 10.1002/art.20741

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  • An association of IgG anti-laminin-1 autoantibodies with endometriosis in infertile patients Reviewed

    J Inagaki, M Sugiura-Ogasawara, M Nomizu, M Nakatsuka, K Ikuta, N Suzuki, K Kaihara, K Kobayashi, T Yasuda, Y Shoenfeld, K Aoki, E Matsuura

    HUMAN REPRODUCTION   18 ( 3 )   544 - 549   2003.3

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

    BACKGROUND: Laminin-1, a multifunctional glycoprotein of the basement membrane, is thought to be important in embryogenesis, embryonic implantation, and placentation. We recently showed that serum IgG anti-laminin-1 autoantibodies (auto-Abs) are associated with recurrent first-trimester miscarriages. The present study assessed the clinical significance of anti-laminin-1 Abs with infertility, accompanied with or without endometriosis. METHODS: Sixty-eight infertile patients who underwent laparoscopy or laparotomy and 39 healthy non-pregnant women were tested for IgG anti-laminin-1 Abs. The association between the Abs and endometriosis was analysed. The presence of laminin-1 mRNA was detected in endometriotic lesions. RESULTS: Twenty infertile patients were positive for anti-laminin-1 Abs. The Ab levels in those patients were significantly higher than those in healthy non-pregnant women (P = 0.0005). The presence of the Abs was significantly associated with endometriosis in those patients (P = 0.0096). The Abs recognized a particular domain, i.e., the laminin-alpha1 chain G domain. mRNA encoding laminin-alpha1, -beta1, and -gamma1 chains was expressed in 90% of endometriotic lesions. CONCLUSIONS: IgG anti-laminin-1 Abs were significantly associated with endometriosis in infertile patients. The Abs might be clinically important in the development of autoimmune-mediated reproductive failures and the assessment of the Abs may provide a novel non-invasive diagnosis of endometriosis.

    DOI： 10.1093/humrep/deg148

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  • IgG anti-laminin-1 autoantibody and recurrent miscarriages. Reviewed

    Inagaki J, Matsuura E, Nomizu M, Sugiura-Ogasawara M, Katano K, Kaihara K, Kobayashi K, Yasuda T, Aoki K

    American journal of reproductive immunology (New York, N.Y. : 1989)   45   232 - 238   2001.4

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  • Proteolytic cleavage of beta 2-glycoprotein I: reduction of antigenicity and the structural relationship Reviewed

    E Matsuura, J Inagaki, H Kasahara, D Yamamoto, T Atsumi, K Kobayashi, K Kaihara, DD Zhao, K Ichikawa, A Tsutsumi, T Yasuda, DA Triplett, T Koike

    INTERNATIONAL IMMUNOLOGY   12 ( 8 )   1183 - 1192   2000.8

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

    Binding of beta(2)-glycoprotein I (beta(2)-GPI)-dependent anticardiolipin antibodies (aCL) derived from antiphospholipid syndrome (APS) is significantly reduced in aCL ELISA due to loss of the phospholipid (PL) binding property of beta(2)-GPI by plasmin treatment. In the present study, the treatment generated a nicked form of alpha(2)-GPI and resulted in loss of antigenicity for the autoantibodies detected in ELISA, using an PP-GPI directly adsorbed polyoxygenated carboxylated plate, the assay system of which was not related to PL binding. The nicked form bound to neither Cu2+-oxidized low-density lipoprotein (oxLDL) nor to beta(2)-GPI-specific lipid ligands isolated from oxLDL, the result being a complete loss of subsequent binding of anti-pg-GPI autoantibodies. The conformational change in the nicked domain V was predicted from its intact structure determined by an X-ray analysis (implemented in Protein Data Bank: 1C1Z), molecular modeling and epitope mapping of a monoclonal anti-beta(2)-GPI antibody, i.e. Cof-18, which recognizes the related structure. The analysis revealed that novel hydrophobic and electrostatic interactions appeared in domain V after the cleavage, thereby affecting the PL binding of beta(2)-GPI, Such a conformational change may have important implications for exposure of cryptic epitopes located in the domains such as domain IV.

    DOI： 10.1093/intimm/12.8.1183

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  • 抗リン脂質抗体と動脈硬化 Invited

    松浦栄次, 小林和子, 笠原順子, 貝原恵子, 小池隆夫

    リウマチ科   24 ( 4 )   378 - 384   2000

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    Language：Japanese  

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  • 心筋の伸展刺激誘発性ROS産生のメカノトランスダクション

    千葉弓子, 貝原恵子, 入部玄太郎

    日本生体医工学会大会プログラム・抄録集(Web)   63rd   2024

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  • 蛍光遠心顕微鏡を用いた過重力下のオルガネラ挙動およびカルシウム動態

    貝原恵子, 松浦宏冶, 成瀬恵治

    日本生体医工学会大会プログラム・抄録集(Web)   63rd   2024

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  • Single cell mechanics of human cardiomyocytes assessed by cellular force-length relationships(タイトル和訳中)

    Komatsu Hiroaki, Kotani Yasuhiro, Kaihara Keiko, Naruse Keiji, Kasahara Shingo, Iribe Gentaro

    The Journal of Physiological Sciences   73 ( Suppl.1 )   108 - 108   2023.5

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  • 新たな蛍光顕微鏡を用いた過重力下のオルガネラ挙動の解明

    貝原恵子, 松浦宏治, 成瀬恵治

    日本生体医工学会大会プログラム・抄録集(Web)   62nd   2023

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  • マウス心室心筋細胞におけるNOX4-TRPV1相互作用の単一細胞力学に対する役割(Role of NOX4-TRPV1 interaction on single cell mechanics in mouse ventricular cardiomyocytes)

    Kaihara Keiko, Naruse Keiji, Iribe Gentaro

    The Journal of Physiological Sciences   72 ( Suppl.1 )   117 - 117   2022.12

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  • マウス心筋細胞で認める高静水圧誘発性緩徐収縮(High hydrostatic pressure induces slow contraction in mouse cardiomyocytes)

    Yamaguchi Yohei, Nishiyama Masayoshi, Kai Hiroaki, Kaneko Toshiyuki, Kaihara Keiko, Iribe Gentaro, Takai Akira, Naruse Keiji, Morimatsu Masatoshi

    生物物理   62 ( Suppl.1-2 )   S458 - S458   2022.8

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  • 過重力下における細胞内小器官観測可能な新たな蛍光遠心顕微鏡の開発

    貝原恵子, 成瀬恵治

    日本生体医工学会大会プログラム・抄録集(Web)   61st   2022

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  • NOX4由来のROSが心筋細胞メカニクスに及ぼす影響(Effects of NOX4-induced ROS on single cell mechanics in mouse ventricular cardiomyocytes)

    Kaihara Keiko, Naruse Kenji, Iribe Gentaro

    The Journal of Physiological Sciences   71 ( Suppl.1 )   163 - 163   2021.8

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  • マウスにおいてNADPHオキシダーゼ4が心筋細胞メカニクスに及ぼす影響(Effects of NADPH oxidase (NOX) 4 on single cell mechanics in mouse ventricular cardiomyocytes)

    Kaihara Keiko, Naruse Keiji, Iribe Gentaro

    The Journal of Physiological Sciences   70 ( Suppl.1 )   S119 - S119   2020.3

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  • Involvement of myocardial acute stretch-induced ROS production in development of heart failure

    KAIHARA Keiko, NARUSE Keiji, IRIBE Gentaro

    日本生体医工学会大会プログラム・抄録集(Web)   59th   2020

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  • 心筋細胞におけるストレッチ誘発性ミトコンドリア過分極に関するパネキシンヘミチャネルの役割(Role of pannexin hemichannel on stretch-induced mitochondrial hyperpolarization in cardiomyocytes)

    Katsura Daisuke, Iribe Gentaro, Kaihara Keiko, Naruse Keiji

    The Journal of Physiological Sciences   69 ( Suppl.1 )   S202 - S202   2019.6

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  • 心筋細胞メカニクスにNADPHオキシダーゼ4が及ぼす影響(Single cell mechanics effects of NADPH oxidase(NOX) 4 in mouse ventricular cardiomyocytes)

    Kaihara Keiko, Iribe Gentaro, Kai Hiroaki, Naruse Keiji

    生物物理   58 ( Suppl.1-2 )   S431 - S431   2018.8

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  • 伸展刺激誘発性の活性酸素がマウス心筋calciumハンドリングに及ぼす影響(Effects of stretch-induced reactive oxygen species on calcium handling in mouse ventricular cardiomyocytes)

    Kai Hiroaki, Iribe Gentaro, Kaihara Keiko, Yamaguchi Yohei, Naruse Keiji

    The Journal of Physiological Sciences   68 ( Suppl.1 )   S142 - S142   2018.3

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  • 伸展刺激誘発性活性酸素がマウス心室心筋細胞の単細胞機構に及ぼす影響(Effects of stretch-induced reactive oxygen species on single cell mechanics in mouse ventricular cardiomyocytes)

    Kaihara Keiko, Iribe Gentaro, Hayama Yohei, Kai Hiroaki, Naruse Keiji

    The Journal of Physiological Sciences   68 ( Suppl.1 )   S118 - S118   2018.3

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  • Single cell mechanics effects of NADPH oxidase (NOX) 4 in mouse ventricular cardiomyocytes

    KAIHARA Keiko, IRIBE Gentaro, KAI Hiroaki, NARUSE Keiji

    生物物理(Web)   58 ( Supplement 1-2 )   2018

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  • 拡張型心筋症における心筋細胞活性酸素産生の伸展感受性(Stretch-induced increase in reactive oxygen species production in dilated cardiomyopathy)

    Kaihara Keiko, Naruse Keiji, Iribe Gentarou

    The Journal of Physiological Sciences   67 ( Suppl.1 )   S120 - S120   2017.3

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  • 伸展刺激誘発性ROS産生におけるミトコンドリアの役割

    貝原 恵子, 成瀬 恵治, 入部 玄太郎

    日本生理学雑誌   79 ( 1 )   42 - 43   2017.2

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  • 心筋の伸展刺激誘発性の活性酸素産生増加における呼吸鎖複合体の役割(Role of respiratory chain complexes in myocardial stretch-induced increase in reactive oxygen species)

    Kaihara Keiko, Naruse Keiji, Iribe Gentaro

    The Journal of Physiological Sciences   66 ( Suppl.1 )   S97 - S97   2016.3

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  • 心筋細胞におけるTRPC3を介した伸展刺激感知機構(TRPC3 contributes to a slow force response to stretch on mice cardiomyocytes)

    Yamaguchi Yohei, Iribe Gentaro, Kaihara Keiko, Naruse Keiji

    The Journal of Physiological Sciences   66 ( Suppl.1 )   S76 - S76   2016.3

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  • 自己集合性ペプチドハイドロゲル内で三次元培養された細胞への機械刺激

    永井 祐介, 横井 秀典, 貝原 恵子, 成瀬 恵治

    岡山医学会雑誌   126 ( 1 )   7 - 10   2014.4

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  • 伸展刺激によるカルシウムスパーク増加におけるミトコンドリアの役割(Role of mitochondria on stretch-induced increase in calcium spark rate)

    Kaihara Keiko, Naruse Keiji, Iribe Gentaro

    The Journal of Physiological Sciences   64 ( Suppl.1 )   S129 - S129   2014.3

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  • Effects of axial stretch on mitochondrial reactive oxygen species in cardiac myocytes

    IRIBE Gentaro, KAIHARA Keiko, NARUSE Keiji

    日本生体医工学会大会プログラム・論文集(CD-ROM)   53rd   2014

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  • 伸展刺激誘発性カルシウムスパーク増加におけるミトコンドリアの役割

    貝原恵子, 成瀬恵治, 入部玄太郎

    日本生理学雑誌   76 ( 4 (Web) )   2014

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  • 自己集合性ペプチドゲルを用いた3次元培養ストレッチシステムの開発

    永井祐介, 永井祐介, 徳山英二郎, 横井秀典, 貝原恵子, 高橋賢, 成瀬恵治

    再生医療   12   2013

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  • 単離心筋細胞への高伸展刺激負荷のための新たな細胞保持系の確立

    金子 智之, 入部 玄太郎, 貝原 恵子, 成瀬 恵治

    生体医工学   50 ( 4 )   398 - 398   2012.8

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  • Effects of azelnidipine on single cardiomyocyte mechanics

    G. Iribe, K. Kaihara, H. Ito, K. Naruse

    EUROPEAN HEART JOURNAL   32   887 - 887   2011.8

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  • 心室筋細胞の収縮性に対するアゼルニジピンの影響

    貝原恵子, 入部玄太郎, 成瀬恵治

    日本生理学雑誌   73 ( 2 )   2011

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  • 0235 Development of new peptide scaffold for 3-D cell culturing under mechanical stimulation

    NAGAI Yusuke, KAIHARA Keiko, YOKOI Hidenori, UESUGI Koji, NARUSE Keiji

    2009 ( 22 )   219 - 219   2010.1

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    Language：Japanese   Publisher：The Japan Society of Mechanical Engineers  

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  • 機械的刺激下での三次元細胞培養のための自己集合性ペプチドナノ繊維足場(Self-assembling peptide nanofiber scaffold for 3-D cell culturing under mechanical stimulation)

    Nagai Yusuke, Kaihara Keiko, Yokoi Hidenori, Uesugi Koji, Naruse Keiji

    Organ Biology   16 ( 1 )   149 - 149   2009.4

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  • 孵化後のトリ心筋SAKCAチャネルの伸展感受性

    入部玄太郎, JIN Honghua, 永井祐介, 貝原恵子, 成瀬恵治

    日本生体医工学会大会プログラム・論文集(CD-ROM)   48th   2009

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  • 志賀毒素誘導の腎上皮様Vero細胞のアポトーシスにおけるAktの関与(Involvement of Akt in Shiga toxin-induced apoptosis of renal epithelial cells)

    Kobuchi Hirotsugu, Kaihara Keiko, Utsumi Kozo, Yasuda Tatsuji

    生化学   76 ( 8 )   1089 - 1089   2004.8

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  • 志賀毒素はJNK依存的Bcl-2リン酸化を介してアポトーシスを誘導する

    小淵浩嗣, 貝原恵子, 保田立二

    日本細菌学雑誌   59 ( 1 )   2004

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  • 志賀毒素誘導アポトーシスにおけるJNK活性化の意義

    小淵浩嗣, 貝原恵子, 内海耕ぞう, 保田立二

    生化学   76 ( 3 )   2004

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  • 志賀毒素のアポトーシス誘導機構におけるJNKの関与

    小淵浩嗣, 貝原恵子, 保田立二

    日本細菌学雑誌   58 ( 1 )   2003

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  • 志賀毒素によるJNKを介したアポトーシス誘導

    小淵浩嗣, 貝原恵子, 内海耕ぞう, 保田立二

    生化学   74 ( 8 )   2002

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  • IgG抗ラミニン-1自己抗体 反復流産及び子宮内膜症の危険因子

    稲垣 純子, 松浦 栄次, 小笠原 真弓, 野水 基義, 片野 衣江, 貝原 恵子, 小林 和子, 保田 立二, 青木 耕治

    日本免疫学会総会・学術集会記録   31   76 - 76   2001.12

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  • β2-グリコプロテインIに特異的な酸化脂質リガンドと自己抗体の動脈硬化進展への関与

    劉 慶平, 松浦 栄次, 小林 和子, 稲垣 純子, 貝原 恵子, 笠原 順子, 保田 立二, 小池 隆夫

    日本免疫学会総会・学術集会記録   31   76 - 76   2001.12

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  • A specific ligand for β<inf>2</inf>-glycoprotein I mediates autoantibody-dependent uptake of oxidized low density lipoprotein by macrophages

    Kazuko Kobayashi, Eiji Matsuura, Qingping Liu, Jun Ichi Furukawa, Keiko Kaihara, Junko Inagaki, Tatsuya Atsumi, Nobuo Sakairi, Tatsuji Yasuda, Dennis R. Voelker, Takao Koike

    Journal of Lipid Research   42   697 - 709   2001.6

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    β2-Glycoprotein I (β2-GPI) is a major antigen for antiphospholipid antibodies (Abs) present in patients with the antiphospholipid syndrome (APS). We previously reported that β2-GPI specifically binds to oxidized low density lipoprotein (oxLDL), but not to native low density lipoprotein (LDL). In the present study, a ligand specific for β2-GPI, oxLig-1, was purified from the extracted lipids of oxLDL. The structure of oxLig-1 was shown to be identical to that of synthesized 7-ketocholesteryl-9-carboxynonanoate by mass spectroscopy and nuclear magnetic resonance analyses. Both purified and synthesized oxLig-1 were recognized by β2-GPI and subsequently by anti-β2-GPI auto-Abs, either in enzyme-linked immunosorbent assay (ELISA) or in ligand blot analysis. Binding of liposomes containing oxLig-1 (oxLig-1-liposomes) to mouse macrophages, J774A.1 cells, was relatively low, as compared with that of phosphatidylserine (PS)-liposomes. In contrast, binding of oxLig-1-liposomes was enhanced more than 10-fold in the presence of both β2-GPI and an anti-β2-GPI auto-Ab (WB-CAL-1), derived from (NZW x BXSB) F1 mouse, an animal APS model. Anti-β2-GPI auto-Abs derived from APS patients with episodes of arterial thrombosis were detected in ELISA, using a solid phase oxLig-1 complexed with β2-GPI. We suggest that autoimmune atherogenesis linked to β2-GPI interaction with oxLDL and Abs may be present in APS.

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  • 抗リン脂質抗体症候群患者血清中に抗スルファチド抗体の特異性

    貝原 恵子, 松浦 栄次, 小林 和子, 稲垣 純子, 劉 慶平, 保田 立二, 宮脇 昌二, 小池 隆夫

    リウマチ   41 ( 2 )   392 - 392   2001.4

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  • 抗リン脂質抗体症候群における動脈硬化発症への酸化コレステロールエステルの関与

    小林 和子, 松浦 栄次, 劉 慶平, 貝原 恵子, 稲垣 純子, 保田 立二, 小池 隆夫

    リウマチ   41 ( 2 )   391 - 391   2001.4

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  • IgG anti-laminin-1 autoantibody and recurrent miscarriages

    Junko Inagaki, Eiji Matsuura, Eiji Matsuura, Motoyoshi Nomizu, Mayumi Sugiura-Ogasawara, Kinue Katano, Keiko Kaihara, Kazuko Kobayashi, Tatsuji Yasuda, Koji Aoki

    American Journal of Reproductive Immunology   45   232 - 238   2001.1

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    Problem: The present study assesses the clinical significance of anti-laminin-1 auto-antibodies (auto-Abs) in recurrent miscarriages. Method of study: A total of 207 recurrent aborters with a history of two or more consecutive first-trimester miscarriages were tested for the presence of anti-laminin-1 Abs, β2-glycoprotein I-dependent anticardiolipin Abs, lupus anticoagulants, anti-DNA Abs, and anti-nuclear Abs, before they had conceived again. Recurrent aborters then were followed up during subsequent pregnancies and their outcomes were evaluated relative to their blood test results prior to pregnancy. Results: Fifty-five (31.1%) women out of 177 recurrent aborters were positive for IgG anti-laminin-1 auto-Abs. The levels of IgG anti-laminin-1 auto-Abs in recurrent aborters were significantly higher than those in healthy pregnant women and in healthy non-pregnant women (P = 0.0043 and 0.0073, respectively). The live birth rate of subsequent pregnancies in IgG anti-laminin-1 auto-Abs-positive recurrent aborters was significantly lower than the IgG anti-laminin-1 auto-Abs-negative recurrent aborters (P = 0.0320). There were no specifically significant relationships observed between IgG anti-laminin-1 auto-Abs and other tested auto-Abs. Conclusion: IgG anti-laminin-1 auto-Abs are associated with recurrent miscarriages and the subsequent pregnancy outcome of recurrent aborters.

    DOI： 10.1111/j.8755-8920.2001.450406.x

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  • 抗リン脂質抗体症候群における血中酸化LDLの臨床的意義

    笠原 順子, 松浦 栄次, 趙 丹丹, 小林 和子, 劉 慶平, 貝原 恵子, 稲垣 純子, 保田 立二, 槇野 博史

    日本免疫学会総会・学術集会記録   30   108 - 108   2000.11

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  • β2グリコプロテインI valine/leucine247遺伝子多型が抗β2-glycoprotein I抗体の結合性に与える影響

    保田 晋助, 渥美 達也, 松浦 栄次, 貝原 恵子, 竹内 理恵, 堀田 哲也, 三好 義範, 小椋 庸隆, 天崎 吉晴, 市川 健司

    日本免疫学会総会・学術集会記録   30   104 - 104   2000.11

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  • 自己免疫疾患患者おける抗スルファチド抗体の出現 SLE及び抗リン脂質抗体症候群における解析

    貝原 恵子, 松浦 栄次, 小林 和子, 稲垣 純子, 劉 慶平, 保田 立二, 宮脇 昌二, 小池 隆夫

    日本免疫学会総会・学術集会記録   30   107 - 107   2000.11

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  • 抗リン脂質抗体症候群における動脈血栓への抗β2-グリコプロテインI自己抗体の関与

    小林 和子, 松浦 栄次, 劉 慶平, 貝原 恵子, 稲垣 純子, 保田 立二, 小池 隆夫

    日本免疫学会総会・学術集会記録   30   107 - 107   2000.11

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  • Valine/leucine(247) polymorphism of beta 2-glycoprotein 1 affects the reactivity of anti-beta 2-glycoprotein 1 antibodies.

    S Yasuda, T Atsumi, K Ichikawa, E Matsuura, K Kaihara, T Yasuda, Y Amasaki, T Koike

    ARTHRITIS AND RHEUMATISM   43 ( 9 )   S404 - S404   2000.9

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  • 抗β2-グリコプロテインI・酸化LDL抗体による動脈硬化の発症機序

    小林 和子, 松浦 栄次, 劉 慶平, 貝原 恵子, 稲垣 純子, 保田 立二, 小池 隆夫

    リウマチ   40 ( 2 )   385 - 385   2000.4

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  • 自己抗原の発現に関与するβ2-グリコプロテインIのドメインIV-V間の相互作用

    貝原 恵子, 松浦 栄次, 山本 大助, 小林 和子, 稲垣 純子, 劉 慶平, 保田 立二, 小池 隆夫

    リウマチ   40 ( 2 )   387 - 387   2000.4

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  • 抗β2-グリコプロテインI抗体の動脈硬化への関与(II) マクロファージによる酸化LDLの取り込みの機序

    小林 和子, 松浦 栄次, 劉 慶平, 貝原 恵子, 稲垣 純子, 保田 立二, 小池 隆夫

    日本免疫学会総会・学術集会記録   29   35 - 35   1999.10

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  • cryptic epitopeの発現に関与するβ2-グリコプロテインIのドメインIV-V間の相互作用

    貝原 恵子, 松浦 栄次, 山本 大助, 小林 和子, 稲垣 純子, 劉 慶平, 保田 立二, 小池 隆夫

    日本免疫学会総会・学術集会記録   29   35 - 35   1999.10

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  • 抗β2-グリコプロテインI抗体の動脈硬化への関与I.酸化LDL由来のリガンドの精製と自己抗体の反応性

    松浦 栄次, 小林 和子, 劉 慶平, 貝原 恵子, 稲垣 純子, 保田 立二, 小池 隆夫

    日本免疫学会総会・学術集会記録   29   35 - 35   1999.10

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  • 抗リン脂質抗体の動脈硬化の進展への関与

    小林 和子, 松浦 栄次, 稲垣 純子, 貝原 恵子, 保田 立二, 小池 隆夫

    リウマチ   39 ( 2 )   322 - 322   1999.4

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  • plasminによる限定分解 自己抗原であるβ2-グリコプロテイン1の抗原性の消失

    松浦 栄次, 稲垣 純子, 小林 和子, 貝原 恵子, 保田 立二, 笠原 英樹, 市川 健司, 堤 明人, 小池 隆夫

    リウマチ   39 ( 2 )   323 - 323   1999.4

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  • 抗β2-グリコプロテインI抗体の反応特異性の解析:酸性リン脂質由来の脂肪酸の関与

    小林 和子, 松浦 栄次, 稲垣 純子, 貝原 恵子, 保田 立二, 小池 隆夫

    日本臨床免疫学会会誌   ( 26回抄録集 )   242 - 242   1998.10

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  • 自己抗原であるβ2-グリコプロテインIの三次構造

    山本 大助, 松浦 栄次, 貝原 恵子, 稲垣 純子, 小林 和子, 保田 立二, 小池 隆夫

    日本臨床免疫学会会誌   ( 26回抄録集 )   239 - 239   1998.10

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  • 自己抗原であるβ2-グリコプロテインIの不活化:plasminによる酵素的開裂に伴う抗原性の消失

    松浦 栄次, 稲垣 純子, 小林 和子, 貝原 恵子, 保田 立二, 山本 大助, 笠原 英樹, 市川 健司, 堤 明人, 小池 隆夫

    日本臨床免疫学会会誌   ( 26回抄録集 )   242 - 242   1998.10

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  • 自己抗原であるβ2-グリコプロテインIの3次構造

    山本大助, 松浦栄次, 貝原恵子, 稲垣純子, 小林和子, 保田立二, 小池隆夫

    日本免疫学会総会・学術集会記録   28   1998

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  • 自己抗原であるβ2-グリコプロテインIの不活化 plasminによる酵素的開裂に伴う抗原性の消失

    松浦栄次, 稲垣純子, 小林和子, 貝原恵子, 保田立二, 山本大助, 笠原英樹, 市川健司, 小池隆夫

    日本免疫学会総会・学術集会記録   28   1998

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  • 抗β2-グリコプロテインI抗体の反応特異性の解析 酸性リン脂質由来の脂肪酸の関与

    小林和子, 松浦栄次, 稲垣純子, 貝原恵子, 保田立二, 小池隆夫

    日本免疫学会総会・学術集会記録   28   1998

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  • Treatment of experimental retrovirus infection by toxin gene binding electropositive electric charge liposome.

    李振泰, 塔郷, 渡来仁, 貝原(細谷)恵子, 小沼操, 柿谷均, 保田立二

    日本分子生物学会年会プログラム・講演要旨集   19th   1996

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Awards

  • コニカミノルタ科学技術振興財団・日本生体医工学会大会奨励賞

    2024.5   第63回日本生体医工学会大会   蛍光遠心顕微鏡を用いた過重力下のオルガネラ挙動およびカルシウム動態

    貝原恵子, 松浦宏冶, 成瀬恵治

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  • 最優秀若手講演奨励賞

    2022.10   第45回日本生体医工学会中国四国支部大会   ヒト単離心筋細胞における長さ張力関係を用いた力学機能評価

    小松弘明, 小谷恭弘, 貝原恵子, 成瀬恵治, 笠原真悟, 入部玄太郎

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  • 若手講演奨励賞

    2019.10   第42回日本生体医工学会中国四国支部大会   心筋バイオメカニクス制御におけるプリン作動性シグナリングの役割

    赤嶺透子, 入部玄太郎, 貝原恵子, 桂大輔, 成瀬恵治

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Research Projects

  • Effects of gravity-mediated mechanotransduction on cardiomyocyte calcium handling

    Grant number：24K15698  2024.04 - 2027.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    貝原 恵子, 成瀬 恵治, 松浦 宏治

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    Grant amount：\4680000 （ Direct expense: \3600000 、 Indirect expense：\1080000 ）

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  • 心筋機械感受性制御におけるROSシグナリングの役割とその心不全治療への展開

    Grant number：21K12640  2021.04 - 2024.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    入部 玄太郎, 山口 陽平, 貝原 恵子, 金子 智之

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    Grant amount：\4290000 （ Direct expense: \3300000 、 Indirect expense：\990000 ）

    本年度は、単離心筋細胞で観察される伸展誘発性ROS産生増加による筋小胞体カルシウムハンドリングの修飾がどのように心筋メカニクスに影響しているかを、野生型およびNOX2ノックアウト（KO）マウス心筋細胞の伸展誘発性カルシウムトランジェント変化、心筋細胞長さ張力関係による力学解析から検討した。
    その結果、心筋細胞の収縮性の指標となる収縮期末長さ張力関係の傾き（最大弾性率）は野生型に比べてNOX2KOマウスでは有意に低下していた。伸展によるカルシウムトランジェント波形は野生型のマウス心筋細胞では変化が無かったが、NOX2KOマウス心筋細胞においては細胞内カルシウム濃度の上昇率が最大に達するまでの時間が伸展によって有意に遅延することが明らかとなった。
    NOX2はリアノジン受容体を刺激することが知られているが、このカルシウムトランジェントの変化がNOX2による伸展誘発性ROS産生の有無によって説明ができるのか、また、この変化がNOX2KOマウス心筋の収縮性低下を説明できるのかをコンピュータシミュレーションによって検討した。心筋細胞数理モデルとしてIribe-Kohl-Nobleモデルを用いた。このリアノジン受容体モデルの活性化レートを上げ、同時にリアノジン受容体からのカルシウムリーク率を上げることでNOX2がリアノジン受容体に及ぼす影響を再現した。前者はカルシウムトランジェントの立ち上がりをやや早め、ピークを上昇させるが、後者はピークを減弱させる効果があり、結果としてピークは変わらず立ち上がりの早いトランジェント波形となった。また、前者は発生張力を増加させる効果があり、後者は発生張力をわずかに減少させる効果があるがその効果は弱く、結果的に収縮力は増加することとなり、細胞実験の結果を再現することができた。

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  • Force-Length Relationによる単離ヒト心筋細胞の機能評価

    Grant number：21K08866  2021.04 - 2024.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    小松 弘明, 貝原 恵子, 入部 玄太郎, 小谷 恭弘

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    Grant amount：\4160000 （ Direct expense: \3200000 、 Indirect expense：\960000 ）

    ラットやマウスにおける心筋細胞の単離操作やそれによって得られた単離心筋細胞の力学実験は安定した成績を収めている。我々は先行研究でForce-Length Control Systemによって単一細胞に分解したマウス心筋細胞を直接的に伸展収縮させることでin vitroで負荷非依存性の心機能評価を行うことを可能とした。我々が多く携わる先天性心疾患患者における余剰心筋にこの技術を応用し、細胞レベルで収縮力を解析する実験を行っている。2021年度においてマウスによる心筋細胞の単離・伸展実験の手技の習得と並行し、ヒト心筋細胞での単離・伸展実験を開始した。これまでで5例のヒト心筋細胞を用いた実験を行い、ヒト心筋細胞の単離は行うことができた。今後、ヒト単離心筋細胞を用いた伸展実験を行う予定である。

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  • Investigation of NOX4-mediated mechanotransduction in mechanically-induced cardiac failure

    Grant number：20K12598  2020.04 - 2023.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    貝原 恵子, 成瀬 恵治, 入部 玄太郎

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    Grant amount：\4290000 （ Direct expense: \3300000 、 Indirect expense：\990000 ）

    全身へのポンプ機能を有する心臓は常に収縮弛緩を繰り返しており、心臓生理を解明する上でメカノトランスダクション（力学刺激を細胞が生理反応に転換する過程の分子機構）を理解することは非常に重要である。一方、疾患や老化等の負のイメージが強い活性酸素（ ROS: Reactive oxygen species ）であるが、実は細胞分化や 免疫などに関与する生命にとって非常に重要な生理活性物質である。現在、我々は独自の単離心筋細胞伸展刺激システムを用いて、細胞伸展負荷時にNOX4（ NADPH Oxidase 4 ）由来のROSが産生され収縮力を上げることを明らかにしているが、そのメカニズムは不明である。また、慢性的なメカニカルストレスに対するNOX4由来のROSが、心疾患へどの様に影響を及ぼしているかも明らかでない。そこで、本研究においては慢性的なメカニカルストレス応答で産生されたNOX4由来のROSが心不全移行に関与しているとの仮説のもと、NOX4を介したメカニカルストレスがカルシウムハンドリングへ及ぼす影響を明らかにするとともに、NOX4由来ROSによる心不全への影響を解明することを目的とし、研究に着手している。 今年度は、NOX4由来ROSの関与が疑われるイオンチャネルTRPV1 ( Transient Receptor Potential Vanilloid 1 ) 経路について阻害剤やノックアウトマウス等を用いて、単一細胞での発生張力の測定を行ったところ、有意な収縮力の低下が明らかとなった。つまり、伸展によって産生されたNOX4由来のROSがTRPV1を活性化し伸展時の収縮力増強に関与している可能性が高いことが示唆されたが、詳細は不明であり、今後の更なる研究が期待される。

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  • Physiological and pathophysiological role of NOX4 in cardiac mechano-transduction

    Grant number：17K01359  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Kaihara Keiko

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    Reactive oxygen species (ROS) synthesized by NADPH oxidase (NOX) in vivo is a very important physiologically active substance. Although, myocardial stretch-induced ROS production via NOX2 modulates Ca2+ handling and cellular contractility, behavior of NOX4 is unknown. In the present study, we investigated the physiological and pathophysiological role of NOX4 in cardiac mechano-transduction.
    Ventricular cells isolated were subjected to 5-10% axial stretch with the cardiomyocyte stretch system, were measured ROS production, Ca2+ spark rate, mitochondrial membrane potential and cellular contractility. Cellular contractility and ROS production were significantly suppressed in NOX2 KO and NOX4 KO, but Ca2+ spark rate was suppressed only in NOX2 KO. The results suggest that role of NOX4 during stretch is different from that of NOX2. On the other hand, from the results of TAC model mice, there was an effect of NOX4 on overload, but details could not be clarified.

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  • Development of a three dimensional stretchcell culture system with a self-assembling peptide scaffold

    Grant number：23650264  2011 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    NARUSE Keiji, KAIHARA Keiko, NAGAI Yusuke

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    Grant amount：\3770000 （ Direct expense: \2900000 、 Indirect expense：\870000 ）

    For effective tissue regeneration, we have developed a three dimensional cell culture system capable of mechanical cell stimulation. The degree of ERK phosphorylation and the cell proliferation ratio of three dimensionally cultured mouse skeletal muscle cells were improved by stretch stimulations in a system composed of newly developed self-assembling peptide gel and stretch chamber. These results demonstrated that the three dimensional stretch cell culture system was able to transmit mechanical stimulation to the cell and control its behaviors such as cell proliferation.

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