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BACKGROUND: Exposure to chronic psychological stress is a risk factor for metabolic cardiovascular disease. Given the important role of lysosomal CTSS (cathepsin S) in human pathobiology, we examined the role of CTSS in stress-related thrombosis, focusing on inflammation, oxidative stress, and apoptosis. METHODS: Six-week-old wild-type mice (CTSS+/+) and CTSS-deficient mice (CTSS-/-) randomly assigned to nonstress and 2-week immobilization stress groups underwent iron chloride3 (FeCl3)-induced carotid thrombosis surgery for morphological and biochemical studies. RESULTS: On day 14 poststress/surgery, stress had increased the lengths and weights of thrombi in the CTSS+/+ mice, plus harmful changes in the levels of PAI-1 (plasminogen activation inhibitor-1), ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 13 motifs), and vWF (von Willebrand factor) and arterial tissue CTSS expression. Compared to the nonstressed CTSS+/+ mice, the stressed CTSS-/- mice had decreased levels of PAI-1, vWF, TNF (tumor necrosis factor)-α, interleukin-1β, toll-like receptor-4, cleaved-caspase 3, cytochrome c, p16INK4A, gp91phox, p22phox, ICAM-1 (intercellular adhesion molecule-1), MCP-1 (monocyte chemoattractant protein-1), MyD88 (myeloid differentiation primary response 88), and MMP (matrix metalloproteinase)-2/-9 and increased levels of ADAMTS13, SOD (superoxide dismutase)-1/-2, eNOS (endothelial NO synthase), p-Akt (phospho-protein kinase B), Bcl-2 (B-cell lymphoma-2), p-GSK3α/β (phospho-glycogen synthase kinases alpha and beta), and p-Erk1/2 (phospho-extracellular signal-regulated kinase 1 and 2) mRNAs and/or proteins. CTSS deletion also reduced the arterial thrombus area and endothelial loss. A pharmacological inhibition of CTSS exerted a vasculoprotective action. In vitro, CTSS silencing and overexpression, respectively, reduced and increased the stressed serum and oxidative stress-induced apoptosis of human umbilical vein endothelial cells, and they altered apoptosis-related proteins. CONCLUSIONS: CTSS inhibition appeared to improve the stress-related thrombosis in mice that underwent FeCl3-induction surgery, possibly by reducing vascular inflammation, oxidative stress, and apoptosis. CTSS could thus become a candidate therapeutic target for chronic psychological stress-related thrombotic events in metabolic cardiovascular disease.

DOI： 10.1161/ATVBAHA.122.318455

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Cathepsins can be found in the extracellular space, cytoplasm, and nucleus. It was initially suspected that the primary physiological function of the cathepsins was to break down intracellular protein, and that they also had a role in pathological processes including inflammation and apoptosis. However, the many actions of cathepsins outside the cell and their complicated biological impacts have garnered much interest. Cathepsins play significant roles in a number of illnesses by regulating parenchymal cell proliferation, cell migration, viral invasion, inflammation, and immunological responses through extracellular matrix remodeling, signaling disruption, leukocyte recruitment, and cell adhesion. In this review, we outline the physiological roles of cathepsins in the extracellular space, the crucial pathological functions performed by cathepsins in illnesses, and the recent breakthroughs in the detection and therapy of specific inhibitors and fluorescent probes in associated dysfunction.

DOI： 10.1016/j.cellsig.2022.110531

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BACKGROUND: Young bone marrow transplantation (YBMT) has been shown to stimulate vascular regeneration in pathological conditions, including ageing. Here, we investigated the benefits and mechanisms of the preventive effects of YBMT on loss of muscle mass and function in a senescence-associated mouse prone 10 (SAMP10) model, with a special focus on the role of growth differentiation factor 11 (GDF-11). METHODS: Nine-week-old male SAMP10 mice were randomly assigned to a non-YBMT group (n = 6) and a YBMT group (n = 7) that received the bone marrow of 8-week-old C57BL/6 mice. RESULTS: Compared to the non-YBMT mice, the YBMT mice showed the following significant increases (all P < 0.05 in 6-7 mice): endurance capacity (>61.3%); grip strength (>37.9%), percentage of slow myosin heavy chain fibres (>14.9-15.9%). The YBMT also increased the amounts of proteins or mRNAs for insulin receptor substrate 1, p-Akt, p-extracellular signal-regulated protein kinase1/2, p-mammalian target of rapamycin, Bcl-2, peroxisom proliferator-activated receptor-γ coactivator (PGC-1α), plus cytochrome c oxidase IV and the numbers of proliferating cells (n = 5-7, P < 0.05) and CD34+/integrin-α7+ muscle stem cells (n = 5-6, P < 0.05). The YMBT significantly decreased the levels of gp91phox, caspase-9 proteins and apoptotic cells (n = 5-7, P < 0.05) in both muscles; these beneficial changes were diminished by the blocking of GDF-11 (n = 5-6, P < 0.05). An administration of mouse recombinant GDF-11 improved the YBMT-mediated muscle benefits (n = 5-6, P < 0.05). Cell therapy with young bone marrow from green fluorescent protein (GFP) transgenic mice exhibited GFP+ myofibres in aged muscle tissues. CONCLUSIONS: These findings suggest that YBMT can prevent muscle wasting and dysfunction by mitigating apoptosis and proliferation via a modulation of GDF-11 signalling and mitochondrial dysfunction in SAMP10 mice.

DOI： 10.1002/jcsm.13058

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BACKGROUND: Chronic psychological stress is a risk factor for kidney disease, including kidney dysfunction and hypertension. Lysosomal CatK (cathepsin K) participates in various human pathobiologies. We investigated the role of CatK in kidney remodeling and hypertension in response to 5/6 nephrectomy injury in mice with or without chronic stress. METHODS: Male 7-week-old WT (wild type; CatK+/+) and CatK-deficient (CatK-/-) mice that were or were not subjected to chronic stress underwent 5/6 nephrectomy. At 8 weeks post-stress/surgery, the stress was observed to have accelerated injury-induced glomerulosclerosis, proteinuria, and blood pressure elevation. RESULTS: Compared with the nonstressed mice, the stressed mice showed increased levels of TLR (Toll-like receptor)-2/4, p22phox, gp91phox, CatK, MMP (matrix metalloproteinase)-2/9, collagen type I and III genes, PPAR-γ (peroxisome proliferator-activated receptor-gamma), NLRP-3 (NOD-like receptor thermal protein domain associated protein 3), p21, p16, and cleaved caspase-8 proteins, podocyte foot process effacement, macrophage accumulation, apoptosis, and decreased levels of Bcl-2 (B cell lymphoma 2) and Sirt1, as well as decreased glomerular desmin expression in the kidneys. These harmful changes were retarded by the genetic or pharmacological inhibition of CatK. Consistently, CatK inhibition ameliorated 5/6 nephrectomy-related kidney injury and dysfunction. In mesangial cells, CatK silencing or overexpression, respectively, reduced or increased the PPAR-γ and cleaved caspase-8 protein levels, providing evidence and a mechanistic explanation of CatK's involvement in PPAR-γ/caspase-8-mediated cell apoptosis in response to superoxide and stressed serum. CONCLUSIONS: These results demonstrate that CatK plays an essential role in kidney remodeling and hypertension in response to 5/6 nephrectomy or stress, possibly via a reduction of glomerular inflammation, apoptosis, and fibrosis, suggesting a novel therapeutic strategy for controlling kidney injury in mice under chronic psychological stress conditions.

DOI： 10.1161/HYPERTENSIONAHA.122.19137

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BACKGROUND: Skeletal muscle mass and function losses in aging individuals are associated with quality of life deterioration and disability. Mesenchymal stromal cells exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in aging-related degenerative disease. METHODS AND RESULTS: We investigated the efficacy of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) on sarcopenia-related skeletal muscle atrophy and dysfunction in senescence-accelerated mouse prone 10 (SAMP10) mice. We randomly assigned 24-week-old male SAMP10 mice to a UC-MSC treatment group and control group. At 12 weeks post-injection, the UC-MSC treatment had ameliorated sarcopenia-related muscle changes in performance, morphological structures, and mitochondria biogenesis, and it enhanced the amounts of proteins or mRNAs for myosin heavy chain, phospho-AMP-activated protein kinase, phospho-mammalian target of rapamycin, phospho-extracellular signal-regulated kinase1/2, peroxisome proliferator-activated receptor-γ coactivator, GLUT-4, COX-IV, and hepatocyte growth factor in both gastrocnemius and soleus muscles, and it reduced the levels of proteins or mRNAs for cathepsin K, cleaved caspase-3/-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, and gp91phox mRNAs. The UC-MSC treatment retarded mitochondria damage, cell apoptosis, and macrophage infiltrations, and it enhanced desmin/laminin expression and proliferating and CD34+/Integrin α7+ cells in both types of skeletal muscle of the SAMP10 mice. In vitro, we observed increased levels of HGF, PAX-7, and MoyD mRNAs at the 4th passage of UC-MSCs. CONCLUSIONS: Our results suggest that UC-MSCs can improve sarcopenia-related skeletal muscle atrophy and dysfunction via anti-apoptosis, anti-inflammatory, and mitochondrial biogenesis mechanisms that might be mediated by an AMPK-PGC1-α axis, indicating that UC-MSCs may provide a promising treatment for sarcopenia/muscle diseases.

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DOI： 10.1002/jcsm.12919

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DOI： 10.1016/j.exger.2021.111590

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DOI： 10.1155/2021/9202990

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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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DOI： 10.3389/fcell.2021.687868

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DOI： 10.1093/ageing/afaa086

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DOI： 10.1253/circj.CJ-19-0325

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DOI： 10.1016/j.ijcard.2017.08.041

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DOI： 10.1002/jcsm.12248

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Frailty is an aging-related medical syndrome which contains the decline in physiological, cognitive, and social reserves abilities. It has been known to be important to early identify and prevent reversible frailty. On the other hand, sarcopenia, the aging-related loss of muscle mass and strength or function is major determinant of the quality of life of elderly and frailty. Recently, the accumulating evidence of the physical frailty concept suggested that it is as a risk factor for the long-term care, leading to be important to extend the healthy lifespan. However, the diagnosis of frailty is not necessarily unified, the molecular mechanism underlying the onset of sarcopenia is not clear, and clinical treatment strategy has not been established. Therefore, the searching and identifying of the biomarkers of the frailty and sarcopenia is very important for the prevention as well as the treatment of the muscle disease, and the further studies will be needed to investigate these issues.

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DOI： 10.1161/JAHA.117.006421

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DOI： 10.1016/j.ijcard.2017.05.062

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DOI： 10.1016/j.atherosclerosis.2017.07.014

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DOI： 10.1161/JAHA.117.006394

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DOI： 10.1002/jcsm.12166.

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DOI： 10.1002/jcsm.12166

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DOI： 10.14336/AD.2016.0920

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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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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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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.

DOI： 10.1038/ncomms4838

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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.

DOI： 10.1016/j.nutres.2014.02.003

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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.

DOI： 10.1161/HYPERTENSIONAHA.110.168385

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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 (gp91phox, p22phox, 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.

DOI： 10.1097/HJH.0b013e328341cedf

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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.

DOI： 10.1111/j.1440-1681.2010.05441.x

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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)-1 alpha-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-1 alpha, 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-1 alpha. All of these effects were diminished by LY294002, an inhibitor of phosphatidylinositol 3-kinase; enhanced by deferoxamine, an HIF-1 alpha 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-1 alpha/vascular endothelial growth factor/MMP-2 pathway in advanced age.

DOI： 10.1161/CIRCULATIONAHA.109.909218

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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.

DOI： 10.1016/j.bbrc.2007.10.027

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2018&ichushi_jid=J02593&link_issn=&doc_id=20180831260005&doc_link_id=10.20837%2F42018091191&url=https%3A%2F%2Fdoi.org%2F10.20837%2F42018091191&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：Japanese   Publisher：(一社)日本老年医学会  

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DOI： 10.3143/geriatrics.55.13

Language：English   Publisher：(一社)日本サルコペニア・フレイル学会  

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Language：Japanese   Publisher：(一社)日本サルコペニア・フレイル学会  

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Language：Japanese   Publisher：(一社)日本サルコペニア・フレイル学会  

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Language：Japanese   Publisher：(一社)日本サルコペニア・フレイル学会  

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Language：Japanese   Publisher：医歯薬出版(株)  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2016&ichushi_jid=J00060&link_issn=&doc_id=20161107020002&doc_link_id=%2Faa7ayuma%2F2016%2F025906%2F003%2F0590-0596%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2016%2F025906%2F003%2F0590-0596%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Lead author  

DOI： https://doi.org/10.20837/1201509051

Language：Japanese   Publisher：(株)医薬ジャーナル社  

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Language：Japanese   Publisher：大阪 : 医薬ジャーナル社  

CiNii Books

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I026740212

Language：Japanese   Publisher：日本基礎老化学会  

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Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：English   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(株)世論時報社  

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Language：Japanese   Publisher：(株)ジェフコーポレーション  

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Language：English   Publisher：(NPO)日本高血圧学会  

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Language：English   Publisher：(一社)日本心臓病学会  

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Language：English   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本東洋医学会  

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Language：Japanese   Publisher：(一社)日本東洋医学会  

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Language：English   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：日本自律神経学会  

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Language：Japanese   Publisher：(一社)日本東洋医学会  

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本東洋医学会  

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：Japanese   Publisher：日本自律神経学会  

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Language：Japanese   Publisher：日本自律神経学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2005&ichushi_jid=J00586&link_issn=&doc_id=20051026430010&doc_link_id=%2Fcj3jirit%2F2005%2F004203%2F003%2F0257-0264%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcj3jirit%2F2005%2F004203%2F003%2F0257-0264%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本東洋医学会  

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Language：Japanese   Publisher：(一社)日本東洋医学会  

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Language：Japanese   Publisher：(一社)日本東洋医学会  

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Language：Japanese   Publisher：(一社)日本東洋医学会  

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Language：Japanese   Publisher：(一社)日本東洋医学会  

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Language：Japanese   Publisher：(一社)日本東洋医学会  

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Language：Japanese   Publisher：(株)現代社  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=1999&ichushi_jid=J00778&link_issn=&doc_id=19991126020001&doc_link_id=9909310&url=https%3A%2F%2Fkango-sakuin.nurse.or.jp%2Fnid%2F9909310&type=%E6%9C%80%E6%96%B0%E7%9C%8B%E8%AD%B7%E7%B4%A2%E5%BC%95Web&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00014_1.gif

Language：Japanese  

CiNii Research

Language：Japanese  

CiNii Research

Language：Japanese  

CiNii Research

Language：Japanese  

CiNii Research

Language：Japanese  

CiNii Research

Language：Japanese  

CiNii Research

Language：English  

CiNii Research

Language：English  

CiNii Research

Language：Japanese  

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

Scopus

PubMed

Language：Japanese  

PubMed

Continuous exercise is essential for healthy aging. In recent years, there have been efforts to enable the elderly to engage in continuous exercise at home by utilizing Information and Communication Technology (ICT) devices. Among ICT devices, smart speakers are gaining attention due to their easy voice control, and applications for smart speakers, operating on their screens, are also being developed to assist with exercise. However, there is still a lack of understanding regarding the most effective features of smart speaker applications that support the continuation of exercise. This study aims to identify the key features for sustaining exercise. We have developed a smart speaker application with two features to support this goal. The first feature provides stamps based on the smart speaker application usage. The second feature suggests personalized exercises based on the user's fitness level. Four elderly women were invited to use the smart speaker application continuously at home and to evaluate the proposed features by a questionnaire. The research result suggests that the proposed features could improve self-efficacy, promoting continuous exercise. It also indicates the need for feature adjustment based on the participant's exercise status.

DOI： 10.1109/GCCE59613.2023.10315332

Scopus

CiNii Research

The galaxy spectra we observe are attenuated by dust, produced in galaxies themselves. However, in studies of galaxy evolution, a genuine galaxy spectrum without attenuation is often needed, and the evolution of the attenuation curve is also fundamental for the investigation for the evolution of dust in galaxies. We show one of the important aspects of dust attenuation, the infrared excessultraviolet spectral slope (IRX-β) relation by using the data from MUSYC and GOODS-Herschel projects. We found that the IRX-β relation does not show significant evolution from z=0 to z3, with a very large scatter.

Scopus

Language：Japanese  

DOI： 10.3143/geriatrics.55.13

PubMed

CiNii Research