記述言語：日本語  

DOI： 10.1155/2021/9202990

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記述言語：日本語   出版者・発行元：International Journal of Molecular Sciences  

RBM10 is an RNA-binding protein that regulates alternative splicing (AS). It localizes to the extra-nucleolar nucleoplasm and S1-1 nuclear bodies (NBs) in the nucleus. We investigated the biological significance of this localization in relation to its molecular function. Our analyses, employing deletion mutants, revealed that RBM10 possesses two S1-1 NB-targeting sequences (NBTSs), one in the KEKE motif region and another in the C2H2 Zn finger (ZnF). These NBTSs act synergistically to localize RBM10 to S1-1 NBs. The C2H2 ZnF not only acts as an NBTS, but is also essential for AS regulation by RBM10. Moreover, RBM10 does not participate in S1-1 NB formation, and without alterations of RBM10 protein levels, its NB-localization changes, increasing as cellular transcriptional activity declines, and vice versa. These results indicate that RBM10 is a transient component of S1-1 NBs and is sequestered in NBs via its NBTSs when cellular transcription decreases. We propose that the C2H2 ZnF exerts its NB-targeting activity when RBM10 is unbound by pre-mRNAs, and that NB-localization of RBM10 is a mechanism to control its AS activity in the nucleus.

DOI： 10.3390/ijms221910526

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記述言語：日本語  

DOI： 10.3389/fcell.2021.687868

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記述言語：日本語  

DOI： 10.1016/j.jamda.2020.06.048

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記述言語：日本語  

DOI： 10.1016/j.jamda.2020.11.023

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記述言語：日本語  

DOI： 10.1093/ageing/afaa086

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記述言語：日本語  

DOI： 10.1097/HJH.0000000000002418

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記述言語：日本語  

DOI： 10.1097/HJH.0000000000002424

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記述言語：日本語  

DOI： 10.1007/s12603-020-1316-5

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記述言語：日本語  

DOI： 10.1161/JAHA.117.005886

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記述言語：日本語  

DOI： 10.1253/circj.CJ-19-0325

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記述言語：日本語  

DOI： 10.1161/JAHA.119.011994

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijcard.2018.05.089

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijcard.2017.08.041

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/jcsm.12248

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記述言語：日本語   出版者・発行元：一般社団法人 日本老年医学会  

<p>サルコペニア（sarcopenia）は，加齢に伴うさまざまな要因により，骨格筋蛋タンパクの合成と分解のアンバランス，筋肉修復能低下などが生じることより発症すると考えているが，その詳細に関して多くは不明である．サルコペニアをはじめとした骨格筋萎縮と機能低下の臨床的重要性が認知されつつあるとともに，骨格筋疾患に関する研究も新たな転換期を迎えている．加齢に伴う骨格筋の形態ならびに機能的変化に基づいたオリジナリティーの高い基礎研究が続々と発表され，従来では考えもし得なかった目覚しい発展を遂げている状況である．加齢による骨格筋疾患（サルコペニア）には骨格筋障害を伴っていることがしばしば多く，治療には骨格筋障害へのアプローチが必要である．サルコペニアの発症機序は多因子である．サルコペニア発症・進展プロセスにおいて骨格筋リモデリングと再生不全は重要であり，蛋白質分解システムの異常，そしてタンパク質合成と分解のアンバランスや骨格筋幹細胞の機能不全など様々な要因が関わっている．本稿では，プロテアーゼ·細胞外マトリックス代謝異常，骨格筋タンパク質合成と分解のアンバランス，骨格筋幹細胞老化・機能不全，炎症亢進，骨格筋細胞増殖とアポトーシスアンバランスならびにミトコンドリア機能不全の多方面から前3者に焦点を当てて，本研究グループの研究成果を交えてサルコペニアの新たな分子機構に関する最近の知見について概説する．</p>

DOI： 10.3143/geriatrics.55.13

PubMed

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/JAHA.117.006421

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijcard.2017.05.062

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.atherosclerosis.2017.07.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/JAHA.117.006394

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/jcsm.12166.

PubMed

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/jcsm.12166

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.14336/AD.2016.0920

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記述言語：日本語   出版者・発行元：Arteriosclerosis, Thrombosis, and Vascular Biology  

Objective - Cathepsin S (CatS) participates in atherogenesis through several putative mechanisms. The ability of cathepsins to modify histone tail is likely to contribute to stem cell development. Histone deacetylase 6 (HDAC6) is required in modulating the proliferation and migration of various types of cancer cells. Here, we investigated the cross talk between CatS and HADC6 in injury-related vascular repair in mice. Approach and Results - Ligation injury to the carotid artery in mice increased the CatS expression, and CatS-deficient mice showed reduced neointimal formation in injured arteries. CatS deficiency decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and toll-like receptor 2 expression in ligated arteries. The genetic or pharmacological inhibition of CatS also alleviated the increased phosphorylation of p38 mitogen-activated protein kinase, Akt, and HDAC6 induced by platelet-derived growth factor BB in cultured vascular smooth muscle cells (VSMCs), and p38 mitogen-activated protein kinase inhibition and Akt inhibition decreased the phospho-HDAC6 levels. Moreover, CatS inhibition caused decrease in the levels of the HDAC6 activity in VSMCs in response to platelet-derived growth factor BB. The HDAC6 inhibitor tubastatin A downregulated platelet-derived growth factor-induced VSMC proliferation and migration, whereas HDAC6 overexpression exerted the opposite effect. Tubastatin A also decreased the intimal VSMC proliferation and neointimal hyperplasia in response to injury. Toll-like receptor 2 silencing decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and VSMC migration and proliferation. Conclusions - This is the first report detailing cross-interaction between toll-like receptor 2-mediated CatS and HDAC6 during injury-related vascular repair. These data suggest that CatS/HDAC6 could be a potential therapeutic target for the control of vascular diseases that are involved in neointimal lesion formation.

DOI： 10.1161/ATVBAHA.115.307110

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PubMed

記述言語：日本語   出版者・発行元：International Journal of Cardiology  

Abstract Background Evidence from human and animal studies has demonstrated elevated levels of the cysteine protease cathepsin S (CatS) in hypoxic atherosclerotic lesions. We hypothesized that silencing of CatS gene would suppress ischemia-induced angiogenic action. Methods and results Left femoral artery ligation-induced ischemia in mice showed the increased expression and activity of CatS in the ischemic muscle. The CatS-deficiency (CatS-/-) mice showed impaired functional recovery following hindlimb ischemia and reduced levels of peroxisome proliferator-activated receptor-γ (PPAR-γ), phospho-Akt (p-Akt), p-endothelial nitric oxide synthase, p-extracellular signal-regulated kinase1/2 (Erk1/2), p-p38 mitogen-activated protein kinase, and vascular endothelial growth factor (VEGF) proteins, as well as reduced levels of matrix metalloproteinase-9 and macrophage infiltration in the ischemic muscles. In vitro, CatS silencing reduced the levels of these targeted essential molecules for angiogenesis and vasculogenesis. Together, the results indicated that the effects of CatS knockdown led to defective endothelial cell invasion, proliferation, and tube formation. This notion was reinforced by the finding that CatS inhibition led to a decreased PPAR-γ level and VEGF/Erk1/2 signaling activation in response to ischemia. CatS-/- resulted in decreased circulating EPC-like CD31+/c-Kit+ cells, accompanied by the reduction of the cellular levels of PPAR-γ, p-Akt, and VEGF induced by ischemic stress. Transplantation of bone-marrow-derived mononuclear cells from CatS+/+ mice restored neovascularization in CatS-/- mice. Conclusions CatS activity controls ischemia-induced neovascularization partially via the modulation of PPAR-γ and VEGF/Akt signaling activation.

DOI： 10.1016/j.ijcard.2015.01.058

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PubMed

記述言語：日本語   出版者・発行元：Nature Communications  

Cysteine proteases play important roles in pathobiology. Here we reveal that cathepsin K (CatK) has a role in ischaemia-induced neovascularization. Femoral artery ligation-induced ischaemia in mice increases CatK expression and activity, and CatK-deficient mice show impaired functional recovery following hindlimb ischaemia. CatK deficiency reduces the levels of cleaved Notch1 (c-Notch1), Hes1 Hey1, Hey2, vascular endothelial growth factor, Flt-1 and phospho-Akt proteins of the ischaemic muscles. In endothelial cells, silencing of CatK mimicked, whereas CatK overexpression enhanced, the levels of c-Notch1 and the expression of Notch downstream signalling molecules, suggesting CatK contributes to Notch1 processing and activates downstream signalling. Moreover, CatK knockdown leads to defective endothelial cell invasion, proliferation and tube formation, and CatK deficiency is associated with decreased circulating endothelial progenitor cells-like CD31 + /c-Kit + cells in mice following hindlimb ischaemia. Transplantation of bone marrow-derived mononuclear cells from CatK +/+ mice restores the impairment of neovascularization in CatK -/- mice. We conclude that CatK may be a potential therapeutic target for ischaemic disease. © 2014 Macmillan Publishers Limited.

DOI： 10.1038/ncomms4838

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記述言語：日本語   出版者・発行元：Nutrition Research  

β-Hydroxy- β-methylbutyrate (HMB) prevents deleterious muscle responses under pathological conditions, including tumor- and chronic steroid therapy-related muscle losses. Here, we investigated the hypothesis that HMB may modulate the balance between protein synthesis and degradation in the PI3K/Akt-mediated mammalian target of rapamycin (mTOR) and FoxO1/FoxO3a-dependent mechanisms in differentiated C2C12 muscle cells. We also tested the effect of HMB on the expression of MuRF-1 and atrogin-1 in response to the inflammatory stress. β-Hydroxy- β-methylbutyrate up-regulated phosphorylation of Akt and mTOR, and these effects were completely abolished in the presence of PI3K inhibitor LY294002. β-Hydroxy- β-methylbutyrate also up-regulated FoxO1 and FoxO3a phosphorylation, and these changes were inhibited by LY294002. Although, unexpectedly, HMB failed to reduce the expressions of atrophy-related atrogin-1 messenger RNA and the protein response to the proinflammatory cytokines tumor necrosis factor α plus interferon γ, HMB did attenuate the MuRF-1 expression. Thus, HMB appears to restore the balance between intracellular protein synthesis and proteolysis, likely via activation of the PI3K/Akt-dependent mTOR and FoxO1/FoxO3a signaling pathway and the reduction of tumor necrosis factor α/interferon γ-induced MuRF-1 expression, thereby ameliorating aging-related muscle atrophy. © 2014 Elsevier Inc.

DOI： 10.1016/j.nutres.2014.02.003

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：Hypertension  

The interactions between the renin-angiotensin system and neovascularization in atherosclerotic plaque development are unclear. We investigated the effects of angiotensin II type 1 receptor antagonism in the pathogenesis of atherosclerosis in apolipoprotein E-deficient (ApoE) mice with a special focus on plaque neovascularization. ApoE mice fed a high-fat diet were randomly assigned to 1 of 2 groups and administered vehicle or olmesartan for 12 weeks. Quantification of plaque areas at the aortic root and in the thoracic and abdominal aorta revealed that, in all 3 of the regions, olmesartan reduced intimal neovessel density and the mRNA levels of toll-like receptor (TLR) 2 and TLR4. Olmesartan increased the levels of collagen and elastin, reduced the level of macrophages in the aortic root, and reduced the mRNA and the activity of matrix metalloproteinase (MMP) 2 in aortic roots and thoracic aortas. Aortic ring assay revealed that olmesartan-treated ApoE mice had a markedly lower angiogenic response than that of untreated ApoE mice. Bone marrow-derived endothelial progenitor cell-like c-Kit cells from olmesartan-treated ApoE mice showed marked impairment of cellular functions and lower expression of TLR2/TLR4 and MMP-2 compared with those of untreated controls. MMP-2 deficiency reduced intimal neovessel density and atherosclerotic lesion formation. Olmesartan and small-interfering RNA targeting TLR2 reduced the levels of TLR2, and MMP-2 mRNA induced angiotensin II in cultured endothelial cells. Angiotensin II type 1 receptor antagonism appears to inhibit intimal neovascularization in ApoE mice, partly by reducing TLR2/TLR4-mediated inflammatory action and MMP activation, thus decreasing atherosclerotic plaque growth and increasing plaque instability. © 2011 American Heart Association, Inc.

DOI： 10.1161/HYPERTENSIONAHA.110.168385

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記述言語：日本語   出版者・発行元：Journal of Hypertension  

Objective: The mineralocorticoid receptor has been implicated in the pathogenesis of chronic cardiorenal disease. Statins improve renal remodeling and dysfunction in patients with proteinuric kidney diseases. We aimed to clarify the beneficial effects and mechanisms of action of statins in renal insufficiency. Methods and Results: Dahl salt-sensitive rats fed a high-salt diet were treated from 12 to 20 weeks of age with vehicle, the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin, the synthetic cathepsin inhibitor E64d, or a low or high dosage of pitavastatin (1 or 3 mg/kg daily). Rats fed a low-salt diet served as controls. Rats on the high-salt diet developed massive proteinuria and glomerulosclerosis; these changes were attenuated by both doses of pitavastatin. The amounts of mRNAs or proteins for mineralocorticoid receptor, angiotensin-converting enzyme, angiotensin II type 1 receptor (AT1R), monocyte chemoattractant protein-1, osteopontin, macrophage infiltration, and NADPH subunits (gp91, p22, and Rac1) were significantly higher in the failing kidneys of vehicle-treated rats than in the kidneys of control rats. Either dose of pitavastatin significantly attenuated these changes. These effects of pitavastatin were mimicked by those of apocynin and E64d. Pretreatment with pitavastatin and apocynin inhibited mRNA and protein of mineralocorticoid receptor induced by angiotensin II in cultured podocytes. Conclusion: The beneficial effects of pitavastatin are likely attributable, at least in part, to attenuation of the mineralocorticoid receptor-dependent inflammatory mediator, matrix protein, and cathepsin expressions induced by AT1R-mediated NADPH oxidase activation in the kidneys of a salt-induced hypertensive Dahl salt-sensitive rat model. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

DOI： 10.1097/HJH.0b013e328341cedf

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：Clinical and Experimental Pharmacology and Physiology  

1. Matrix metalloproteinases (MMP) are associated with the vascular remodelling seen in atherosclerosis and aneurysm. The activation and activity of MMP-2 are regulated by the intrinsic tissue inhibitor of MMP-2 (TIMP-2). The aim of the present study was to examine whether, conversely, MMP-2 can affect the gene and protein expression of TIMP-2. 2. In the present study, we examined the mRNA and protein expression of MMP-2 and TIMP-2 in cultured smooth muscle cells (SMC) from the aortas of MMP-2+/+ and MMP-2 / mice. We also examined the roles of MMP-2 in SMC cellular events. 3. Western blotting showed that less TIMP-2 protein was present in the conditioned medium of MMP-2 / SMC than in that of MMP-2+/+ SMC. Real-time reverse transcription polymerase chain reaction analysis showed that MMP-2 deficiency reduced TIMP-2 mRNA expression in SMC. Recombinant MMP-2 enhanced the expression of TIMP-2 protein in cultured SMC from MMP-2 / mice. Furthermore, a siRNA targeting MMP-2 impaired the gene and protein expression of MMP-2 in cultured SMC from MMP-2+/+ mice. MMP-2 deficiency impaired SMC invasion, but not their proliferation, adhesion or migration. 4. Our findings suggest that MMP-2 is likely to be responsible, at least in part, for regulating TIMP-2 expression and is thus a potential target, in addition to TIMP-2, for therapeutics aimed at preventing cardiovascular remodelling in response to injury. © 2010 The Authors. Clinical and Experimental Pharmacology and Physiology © 2010 Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1440-1681.2010.05441.x

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：Circulation  

Background: Exercise stimulates the vascular response in pathological conditions, including ischemia; however, the molecular mechanisms by which exercise improves the impaired hypoxia-induced factor (HIF)-1α-mediated response to hypoxia associated with aging are poorly understood. Here, we report that swimming training (ST) modulates the vascular response to ischemia in aged (24-month-old) mice. Methods and Results: Aged wild-type mice (MMP-2 +/+) that maintained ST (swimming 1 h/d) from day 1 after surgery were randomly assigned to 4 groups that were treated with either vehicle, LY294002, or deferoxamine for 14 days. Mice that were maintained in a sedentary condition served as controls. ST increased blood flow, capillary density, and levels of p-Akt, HIF-1α, vascular endothelial growth factor, Fit-1, and matrix metalloproteinase-2 (MMP-2+/+) in MMP-2 mice. ST also increased the numbers of circulating endothelial progenitor cells and their function associated with activation of HIF-1α. All of these effects were diminished by LY294002, an inhibitor of phosphatidylinositol 3-kinase; enhanced by deferoxamine, an HIF-1α stabilizer; and impaired by knockout of MMP-2. Finally, bone marrow transplantation confirmed that ST enhanced endothelial progenitor cell homing to ischemic sites in aged mice. Conclusions-: ST can improve neovascularization in response to hypoxia via a phosphatidylinositol 3-kinase-dependent mechanism that is mediated by the HIF-1α/vascular endothelial growth factor/MMP-2 pathway in advanced age. © 2010 American Heart Association, Inc.

DOI： 10.1161/CIRCULATIONAHA.109.909218

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：Biochemical and Biophysical Research Communications  

Neutrophil elastase (NE), a serine protease released from the azurophil granules of activated neutrophil, proteolytically cleaves multiple cytokines, and cell surface proteins. In the present study, we examined whether NE affects the biological abilities of angiogenic growth factors such as basic-fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). NE degraded bFGF and VEGF in a time- and concentration-dependent manner, and these degradations were suppressed by sivelestat, a synthetic inhibitor of NE. The bFGF- or VEGF-mediated proliferative activity of human umbilical vein endothelial cells was inhibited by NE, and the activity was recovered by sivelestat. Furthermore, NE reduced the bFGF- or VEGF-induced tubulogenic response of the mice aortas, ex vivo angiogenesis assay, and these effects were also recovered by sivelestat. Neutrophil-derived NE degraded potent angiogenic factors, resulting in loss of their angiogenic activity. These findings provide additional insight into the role played by neutrophils in the angiogenesis process at sites of inflammation. © 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.10.027

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

CiNii Research

記述言語：日本語  

CiNii Research

記述言語：日本語  

CiNii Research

記述言語：日本語  

CiNii Research

記述言語：日本語  

CiNii Research

記述言語：日本語  

CiNii Research

記述言語：英語  

CiNii Research

記述言語：英語  

CiNii Research

記述言語：日本語  

OBJECTIVE: To investigate the mechanism responsible for the increased cardiac stiffness associated with hypertensive heart failure in Dahl salt-sensitive (DS) rats and the effects of treatment with the combination of a calcium channel blocker [azelnidipine (AZE)] and angiotensin II type 1 receptor blocker [olmesartan (OLM)]. METHODS: DS rats fed a high-salt diet from 7 weeks of age were treated (or not) from 12 to 19 weeks of age with the vasodilator hydralazine, OLM plus AZE, or the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin. Rats fed a low-salt diet served as controls. RESULTS: Treatment with OLM plus AZE attenuated changes in the expression of collagen isoforms and a decrease in the ratio of elastin to collagen in the left ventricle and prevented the increase in myocardial stiffness and diastolic dysfunction in DS rats in a manner independent of the hypotensive effect of these drugs. Such treatment also inhibited the expression and activation of elastolytic proteases (including cathepsins S and K and metalloproteinases-2, -9, and -12), NADPH oxidase-dependent superoxide production, and inflammatory changes in the failing myocardium. All these effects were mimicked by treatment with apocynin. CONCLUSIONS: The changes in collagen isoform expression and the decrease in the elastin to collagen ratio in the failing myocardium likely account for the increase in diastolic stiffness in this model of hypertensive heart failure. Administration of angiotensin receptor and calcium channel blockers prevented these changes in a manner independent of the hypotensive effect of these drugs by inhibiting the increase in elastolytic activity induced by activation of NADPH oxidase. © 2009 Lippincott Williams & Wilkins, Inc.

DOI： 10.1097/FJC.0b013e3181ab371d

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