研究者詳細 - 井上　愛子

Myonectin protects against skeletal muscle dysfunction in male mice through activation of AMPK/PGC1α pathway

Ozaki, Y; Ohashi, K; Otaka, N; Kawanishi, H; Takikawa, T; Fang, LX; Takahara, K; Tatsumi, M; Ishihama, S; Takefuji, M; Kato, K; Shimizu, Y; Bando, YK; Inoue, A; Kuzuya, M; Miura, S; Murohara, T; Ouchi, N

NATURE COMMUNICATIONS 14 巻 ( 1 ) 頁： 4675 2023年8月

記述言語：英語出版者・発行元：Nature Communications

To maintain and restore skeletal muscle mass and function is essential for healthy aging. We have found that myonectin acts as a cardioprotective myokine. Here, we investigate the effect of myonectin on skeletal muscle atrophy in various male mouse models of muscle dysfunction. Disruption of myonectin exacerbates skeletal muscle atrophy in age-associated, sciatic denervation-induced or dexamethasone (DEX)-induced muscle atrophy models. Myonectin deficiency also contributes to exacerbated mitochondrial dysfunction and reduces expression of mitochondrial biogenesis-associated genes including PGC1α in denervated muscle. Myonectin supplementation attenuates denervation-induced muscle atrophy via activation of AMPK. Myonectin also reverses DEX-induced atrophy of cultured myotubes through the AMPK/PGC1α signaling. Furthermore, myonectin treatment suppresses muscle atrophy in senescence-accelerated mouse prone (SAMP) 8 mouse model of accelerated aging or mdx mouse model of Duchenne muscular dystrophy. These data indicate that myonectin can ameliorate skeletal muscle dysfunction through AMPK/PGC1α-dependent mechanisms, suggesting that myonectin could represent a therapeutic target of muscle atrophy.

DOI： 10.1038/s41467-023-40435-2

Cathepsin S deficiency improves muscle mass loss and dysfunction via the modulation of protein metabolism in mice under pathological stress conditions

Wan, Y; Piao, LM; Xu, SN; Inoue, A; Meng, XK; Lei, YN; Huang, Z; Wang, HL; Yue, XL; Shi, GP; Kuzuya, M; Cheng, XW

FASEB JOURNAL 37 巻 ( 8 ) 頁： e23086 2023年8月

記述言語：英語出版者・発行元：FASEB Journal

Cathepsin S (CTSS) is a widely expressed cysteinyl protease that has garnered attention because of its enzymatic and non-enzymatic functions under inflammatory and metabolic pathological conditions. Here, we examined whether CTSS participates in stress-related skeletal muscle mass loss and dysfunction, focusing on protein metabolic imbalance. Eight-week-old male wildtype (CTSS+/+) and CTSS-knockout (CTSS−/−) mice were randomly assigned to non-stress and variable-stress groups for 2 weeks, and then processed for morphological and biochemical studies. Compared with non-stressed mice, stressed CTSS+/+ mice showed significant losses of muscle mass, muscle function, and muscle fiber area. In this setting, the stress-induced harmful changes in the levels of oxidative stress-related (gp91phox and p22phox,), inflammation-related (SDF-1, CXCR4, IL-1β, TNF-α, MCP-1, ICAM-1, and VCAM-1), mitochondrial biogenesis-related (PPAR-γ and PGC-1α) genes and/or proteins and protein metabolism-related (p-PI3K, p-Akt, p-FoxO3α, MuRF-1, and MAFbx1) proteins; and these alterations were rectified by CTSS deletion. Metabolomic analysis revealed that stressed CTSS−/− mice exhibited a significant improvement in the levels of glutamine metabolism pathway products. Thus, these findings indicated that CTSS can control chronic stress-related skeletal muscle atrophy and dysfunction by modulating protein metabolic imbalance, and thus CTSS was suggested to be a promising new therapeutic target for chronic stress-related muscular diseases.

DOI： 10.1096/fj.202300395RRR

CTSS Modulates Stress-Related Carotid Artery Thrombosis in a Mouse FeCl<sub>3</sub> Model

Xu, SN; Piao, LM; Wan, Y; Huang, Z; Meng, XK; Inoue, A; Wang, HL; Yue, XL; Jin, XL; Shi, GP; Kuzuya, M; Cheng, XW

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 43 巻 ( 7 ) 頁： E238 - E253 2023年7月

記述言語：英語出版者・発行元：Arteriosclerosis, Thrombosis, and Vascular Biology

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

Cathepsins in the extracellular space: Focusing on non-lysosomal proteolytic functions with clinical implications

Wang, HL; Inoue, A; Lei, YN; Wu, HX; Hong, L; Cheng, XW

CELLULAR SIGNALLING 103 巻頁： 110531 2023年3月

記述言語：英語出版者・発行元：Cellular Signalling

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

Young bone marrow transplantation prevents aging-related muscle atrophy in a senescence-accelerated mouse prone 10 model

Inoue Aiko, Piao Limei, Yue Xueling, Huang Zhe, Hu Lina, Wu Hongxian, Meng Xiangkun, Xu Wenhu, Yu Chenglin, Sasaki Takeshi, Itakura Kohji, Umegaki Hiroyuki, Kuzuya Masafumi, Cheng Xian Wu

JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE 2022年9月

記述言語：日本語出版者・発行元：Journal of Cachexia, Sarcopenia and Muscle

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

Cathepsin K Deficiency Prevented Kidney Damage and Dysfunction in Response to 5/6 Nephrectomy Injury in Mice With or Without Chronic Stress

Yue Xueling, Piao Limei, Wang Hailong, Huang Zhe, Meng Xiangkun, Sasaki Takeshi, Inoue Aiko, Nakamura Kae, Wan Ying, Xu Shengnan, Shi Guo-Ping, Kim Weon, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu

HYPERTENSION 79 巻 ( 8 ) 頁： 1713 - 1723 2022年8月

記述言語：日本語出版者・発行元：Hypertension

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

Human umbilical cord-derived mesenchymal stromal cells ameliorate aging-associated skeletal muscle atrophy and dysfunction by modulating apoptosis and mitochondrial damage in SAMP10 mice

Piao Limei, Huang Zhe, Inoue Aiko, Kuzuya Masafumi, Cheng Xian Wu

STEM CELL RESEARCH & THERAPY 13 巻 ( 1 ) 頁： 226 2022年6月

記述言語：日本語出版者・発行元：Stem Cell Research and Therapy

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.

DOI： 10.1186/s13287-022-02895-z

Sequestration of RBM10 in Nuclear Bodies: Targeting Sequences and Biological Significance

Cathepsin K activity controls cachexia-induced muscle atrophy via the modulation of IRS1 ubiquitination

Meng Xiangkun, Huang Zhe, Inoue Aiko, Wang Hailong, Wan Ying, Yue Xueling, Xu Shengnan, Jin Xueying, Shi Guo-Ping, Kuzuya Masafumi, Cheng Xian Wu

JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE 13 巻 ( 2 ) 頁： 1197 - 1209 2022年4月

Short- and long-term effects of different exercise programs on the gait performance of older adults with subjective cognitive decline: A randomized controlled trial

Fujita Kosuke, Umegaki Hiroyuki, Makino Taeko, Uemura Kazuki, Hayashi Takahiro, Inoue Aiko, Uno Chiharu, Kitada Tomoharu, Huang Chi Hsien, Shimada Hiroyuki, Kuzuya Masafumi

EXPERIMENTAL GERONTOLOGY 156 巻 2021年12月

Proliferin-1 Ameliorates Cardiotoxin-Related Skeletal Muscle Repair in Mice

Goto Hiroki, Inoue Aiko, Piao Limei, Hu Lina, Huang Zhe, Meng Xiangkun, Suzuki Yusuke, Umegaki Hiroyuki, Kuzuya Masafumi, Cheng Xian Wu

STEM CELLS INTERNATIONAL 2021 巻 2021年11月

Wang Ling-Yu, Xiao Sheng-Jun, Kunimoto Hiroyuki, Tokunaga Kazuaki, Kojima Hirotada, Kimura Masatsugu, Yamamoto Takahiro, Yamamoto Naoki, Zhao Hong, Nishio Koji, Tani Tokio, Nakajima Koichi, Sunami Kishiko, Inoue Akira

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 22 巻 ( 19 ) 2021年10月

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

Statins Mitigate Stress-Related Vascular Aging and Atherosclerosis in apoE-Deficient Mice Fed High Fat-Diet: The Role of Glucagon-Like Peptide-1/Adiponectin Axis

Lei Yanna, Cui Qingsong, Yang Guang, Piao Limei, Inoue Aiko, Wu Hongxian, Li Xiang, Kuzuya Masafumi, Cheng Xian Wu

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY 9 巻 2021年7月

Effect of Various Exercises on Intrinsic Capacity in Older Adults With Subjective Cognitive Concerns

Huang Chi Hsien, Umegaki Hiroyuki, Makino Taeko, Uemura Kazuki, Hayashi Takahiro, Kitada Tomoharu, Inoue Aiko, Shimada Hiroyuki, Kuzuya Masafumi

JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION 22 巻 ( 4 ) 頁： 780 - + 2021年4月

Mental Health Status of the Older Adults in Japan During the COVID-19 Pandemic

Fujita Kosuke, Inoue Aiko, Kuzuya Masafumi, Uno Chiharu, Huang Chi Hsien, Umegaki Hiroyuki, Onishi Joji

JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION 22 巻 ( 1 ) 頁： 220 - 221 2021年1月

Effect of various exercises on frailty among older adults with subjective cognitive concerns: a randomised controlled trial

Huang Chi Hsien, Umegaki Hiroyuki, Makino Taeko, Uemura Kazuki, Hayashi Takahiro, Kitada Tomoharu, Inoue Aiko, Shimada Hiroyuki, Kuzuya Masafumi

AGE AND AGEING 49 巻 ( 6 ) 頁： 1011 - 1019 2020年11月

Increased dipeptidyl peptidase-4 accelerates chronic stress-related thrombosis in a mouse carotid artery model

Jin Xianglan, Jin Chunzi, Nakamura Kae, Jin Tiefeng, Xin Minglong, Wan Ying, Yue Xueling, Jin Shengyu, Wang Hailong, Inoue Aiko, Nan Yongshan, Lin Zhenhua, Kuzuya Masafumi, Cheng Xian Wu

JOURNAL OF HYPERTENSION 38 巻 ( 8 ) 頁： 1504 - 1513 2020年8月

Deficiency of cysteinyl cathepsin K suppresses the development of experimental intimal hyperplasia in response to chronic stress

Meng Xiangkun, Piao Limei, Wang Hailong, Inoue Aiko, Huang Zhe, Jiang Haiying, Nakamura Kae, Sasaki Takeshi, Li Xiang, Xu Wenhu, Yu Chenglin, Hu Lina, Wu Hongxian, Murohara Toyoaki, Shi Guo-Ping, Kuzuya Masafumi, Cheng Xian Wu

JOURNAL OF HYPERTENSION 38 巻 ( 8 ) 頁： 1514 - 1524 2020年8月

Combined Impact of Physical Frailty and Social Isolation on Rate of Falls in Older Adults

Hayashi T., Umegaki Hiroyuki, Makino T., Huang C. H., Inoue A., Shimada H., Kuzuya M.

JOURNAL OF NUTRITION HEALTH & AGING 24 巻 ( 3 ) 頁： 312 - 318 2020年3月

PLF-1 (Proliferin-1) Modulates Smooth Muscle Cell Proliferation and Development of Experimental Intimal Hyperplasia

Hu Lina, Huang Zhe, Ishii Hideki, Wu Hongxian, Suzuki Susumu, Inoue Aiko, Kim Weon, Jiang Haiying, Li Xiang, Zhu Enbo, Piao Limei, Zhao Guangxian, Lei Yanna, Okumura Kenji, Shi Guo-Ping, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu

JOURNAL OF THE AMERICAN HEART ASSOCIATION 8 巻 ( 24 ) 2019年12月

Cathepsin S-Mediated Negative Regulation of Wnt5a/SC35 Activation Contributes to Ischemia-Induced Neovascularization in Aged Mice

Xu Wenhu, Yu Chenglin, Piao Limei, Inoue Aiko, Wang Hailong, Meng Xiangkun, Li Xiang, Cui Lan, Umegaki Hiroyuki, Shi Guo-Ping, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu

CIRCULATION JOURNAL 83 巻 ( 12 ) 頁： 2537 - + 2019年12月

Cathepsin S Deficiency Mitigated Chronic Stress-Related Neointimal Hyperplasia in Mice

Wang Hailong, Meng Xiangkun, Piao Limei, Inoue Aiko, Xu Wenhu, Yu Chenglin, Nakamura Kae, Hu Lina, Sasaki Takeshi, Wu Hongxian, Unno Kazumasa, Umegaki Hiroyuki, Murohara Toyoaki, Shi Guo-Ping, Kuzuya Masafumi, Cheng Xian Wu

JOURNAL OF THE AMERICAN HEART ASSOCIATION 8 巻 ( 14 ) 2019年7月

Cathepsin S Deficiency Impaired Noevascularization in Response to Ischemia via the Activation of Wnt5-SC35 Signaling Pathway in Advanced Age

Xu Wenhu, Yu Chenglin, Piao Limei, Inoue Aiko, Kuzuya Masafumi, Cheng Xian Wu

CIRCULATION 138 巻 2018年11月

ACDF-1Modulates Smooth Muscle Cell Proliferation and Development of Experimental Intimal Hyperplasia

Hu Lina, Ishii Hideki, Wu Hongxian, Suzuki Susumu, Inoue Aiko, Shi Guo-Ping, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu

CIRCULATION 138 巻 2018年11月

Adiponectin/AdipoR1 Signal Inactivation Contributes to Impaired Angiogenesis in Mice of Advanced Age

Piao Limei, Yu Chenglin, Xu Wenhu, Inoue Aiko, Shibata Rei, Ouchi Noriyuki, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu

CIRCULATION 138 巻 2018年11月

Apoptotic Cell-Derived Growth Factor-1 Modulates Noevascularization in Response to Ischemia via the activation of PI3K/Akt/p38MAPK-Depended and -Independent mTOR Signaling Cascades

Yu Chenglin, Piao Limei, Xu Wenhu, Inoue Aiko, Kuzuya Masafumi, Cheng Xian Wu

CIRCULATION 138 巻 2018年11月

Cathepsin S Controls Injury-Related Neointimal Formation in Mice Under Chronic Stress via the Modulation of Inflammation and Immune Action

Wang Hailong, Li Limei, Meng Xiangkun, Inoue Aiko, Shi Guo-Ping, Kuzuya Masafumi, Cheng Xian Wu

CIRCULATION 138 巻 2018年11月

Adiponectin/AdiopR1 signal inactivation contributes to impaired angiogenesis in mice of advanced age

Piao Limei, Yu Chenglin, Xu Wenhu, Inoue Aiko, Shibata Rei, Li Xiang, Nan Yongshan, Zhao Guangxian, Wang Hailong, Meng Xiangkun, Lei Yanna, Goto Hiroki, Ouchi Noriyuki, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu

INTERNATIONAL JOURNAL OF CARDIOLOGY 267 巻頁： 150-155 2018年9月

Response to letter "DPP-4 inhibition as a therapeutic strategy to ameliorate diabetic metabolic memory"

Cheng Xian Wu, Lei Yanna, Piao Limei, Inoue Aiko, Yang Guang, Zhu Enbo, Kuzuya Masafumi

INTERNATIONAL JOURNAL OF CARDIOLOGY 256 巻頁： 17-17 2018年4月

Cathepsin K activity controls cardiotoxin-induced skeletal muscle repair in mice

Ogasawara Shinyu, Cheng Xian Wu, Inoue Aiko, Hu Lina, Piao Limei, Yu Chenglin, Goto Hiroki, Xu Wenhu, Zhao Guangxian, Lei Yanna, Yang Guang, Kimura Kaoru, Umegaki Hiroyuki, Shi Guo-Ping, Kuzuya Masafumi

JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE 9 巻 ( 1 ) 頁： 160 - 175 2018年2月

サルコペニアの分子メカニズム

井上愛子, 成憲武, 五籐大貴, 葛谷雅文

日本老年医学会雑誌 55 巻 ( 1 ) 頁： 13 - 24 2018年

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

Cathepsin S Activity Controls Injury-Related Vascular Repair in Mice via the TLR2-Mediated p38MAPK and PI3K-Akt/p-HDAC6 Signaling Pathway

CiNii Research

Chronic Psychological Stress Accelerates Vascular Senescence and Impairs Ischemia-Induced Neovascularization: The Role of Dipeptidyl Peptidase-4/Glucagon-Like Peptide-1-Adiponectin Axis

Piao Limei, Zhao Guangxian, Zhu Enbo, Inoue Aiko, Shibata Rei, Lei Yanna, Hu Lina, Yu Chenglin, Yang Guang, Wu Hongxian, Xu Wenhu, Okumura Kenji, Ouchi Noriyuki, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu

JOURNAL OF THE AMERICAN HEART ASSOCIATION 6 巻 ( 10 ) 2017年10月

Increased dipeptidyl peptidase-4 accelerates diet-related vascular aging and atherosclerosis in ApoE-deficient mice under chronic stress

Lei Yanna, Yang Guang, Hu Lina, Piao Limei, Inoue Aiko, Jiang Haiying, Sasaki Takeshi, Zhao Guangxian, Yisireyili Maimaiti, Yu Chenglin, Xu Wenhu, Takeshita Kyosuke, Okumura Kenji, Kuzuya Masafumi, Cheng Xian Wu

INTERNATIONAL JOURNAL OF CARDIOLOGY 243 巻頁： 413-420 2017年9月

Exenatide mitigated diet-induced vascular aging and atherosclerotic plaque growth in ApoE-deficient mice under chronic stress

Yang Guang, Lei Yanna, Inoue Aiko, Piao Limei, Hu Lina, Jiang Haiying, Sasaki Takeshi, Wu Hongxian, Xu Wenhu, Yu Chenglin, Zhao Guangxian, Ogasawara Shinyu, Okumura Kenji, Kuzuya Masafumi, Cheng Xian-Wu

ATHEROSCLEROSIS 264 巻頁： 1-10 2017年9月

Dipeptidyl Peptidase-4 Regulates Hematopoietic Stem Cell Activation in Response to Chronic Stress

Zhu Enbo, Hu Lina, Wu Hongxian, Piao Limei, Zhao Guangxian, Inoue Aiko, Kim Weon, Yu Chenglin, Xu Wenhu, Bando Yasuko K., Li Xiang, Lei Yanna, Hao Chang-Ning, Takeshita Kyosuke, Kim Woo-Shik, Okumura Kenji, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu

JOURNAL OF THE AMERICAN HEART ASSOCIATION 6 巻 ( 7 ) 2017年7月

Exercise restores muscle stem cell mobilization, regenerative capacity and muscle metabolic alterations via adiponectin/AdipoR1 activation in SAMP10 mice 査読有り

Aiko Inoue, Xian Wu Cheng, Zhe Huang, Lina Hu, Ryosuke Kikuchi, Haiying Jiang, Limei Piao,Takeshi Sasaki, Kohji Itakura, Hongxian Wu, Guangxian Zhao, Yanna Lei, Guang Yang, Enbo Zhu, Xiang Li, Kohji Sato, Teruhiko Koike, Masafumi Kuzuya.

Journal of Cachexia, Sarcopenia and Muscle 8 巻 ( 3 ) 頁： 370-385 2017年6月

Exercise restores muscle stem cell mobilization, regenerative capacity and muscle metabolic alterations via adiponectin/AdipoR1 activation in SAMP10 mice

Inoue Aiko, Cheng Xian Wu, Huang Zhe, Hu Lina, Kikuchi Ryosuke, Jiang Haiying, Piao Limei, Sasaki Takeshi, Itakura Kohji, Wu Hongxian, Zhao Guangxian, Lei Yanna, Yang Guang, Zhu Enbo, Li Xiang, Sato Kohji, Koike Teruhiko, Kuzuya Masafumi

JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE 8 巻 ( 3 ) 頁： 370 - 385 2017年6月

The Soluble VEGF Receptor sFlt-1 Contributes to Impaired Neovascularization in Aged Mice

Zhao Guangxian, Cheng Xian W., Piao Limei, Hu Lina, Lei Yanna, Yang Guang, Inoue Aiko, Ogasawara Shinyu, Wu Hongxian, Hao Chang-Ning, Okumura Kenji, Kuzuya Masafumi

AGING AND DISEASE 8 巻 ( 3 ) 頁： 287-300 2017年6月

Wu Hongxian, Cheng Xian Wu, Hu Lina, Takeshita Kyosuke, Hu Chen, Du Qiuna, Li Xiang, Zhu Enbo, Huang Zhe, Yisireyili Maimaiti, Zhao Guangxian, Piao Limei, Inoue Aiko, Jiang Haiying, Lei Yanna, Zhang Xiaohong, Liu Shaowen, Dai Qiuyan, Kuzuya Masafumi, Shi Guo-Ping, Murohara Toyoaki

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 36 巻 ( 8 ) 頁： 1549 - 1557 2016年8月

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

Cathepsin S activity controls ischemia-induced neovascularization in mice

Li Xiang, Cheng Xian Wu, Hu Lina, Wu Hongxian, Guo-Ping, Hao Chang-Ning, Jiang Haiying, Zhu Enbo, Huang Zhe, Inoue Aiko, Sasaki Takeshi, Du Qiuna, Takeshita Kyosuke, Okumura Kenji, Murohara Toyoaki, Kuzuya Masafumi

INTERNATIONAL JOURNAL OF CARDIOLOGY 183 巻頁： 198 - 208 2015年3月

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

Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia

Jiang Haiying, Cheng Xian Wu, Shi Guo-Ping, Hu Lina, Inoue Aiko, Yamamura Yumiko, Wu Hongxian, Takeshita Kyosuke, Li Xiang, Huang Zhe, Song Haizhen, Asai Masashi, Hao Chang-Ning, Unno Kazumasa, Koike Teruhiro, Oshida Yoshiharu, Okumura Kenji, Murohara Toyoaki, Kuzuya Masafumi

NATURE COMMUNICATIONS 5 巻頁： 3838 2014年6月

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

beta-Hydroxy-beta-methylbutyrate facilitates PI3K/Akt-dependent mammalian target of rapamycin and FoxO1/3a phosphorylations and alleviates tumor necrosis factor alpha/interferon gamma-induced MuRF-1 expression in C2C12 cells

Kimura Kaoru, Cheng Xian Wu, Inoue Aiko, Hu Lina, Koike Teruhiko, Kuzuya Masafumi

NUTRITION RESEARCH 34 巻 ( 4 ) 頁： 368 - 374 2014年4月

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

Angiotensin Type 1 Receptor Blocker Reduces Intimal Neovascularization and Plaque Growth in Apolipoprotein E-Deficient Mice

Cathepsin K-Mediated Noich1 Activation Contributes to Neovascularization in Response to Hypoxia

Hu Lina, Cheng Xian Wu, Shi Guo-Ping, Jang Haiying, Inoue Aiko, Yamamura Yumiko, Wu Hongxian, Takeshita Kyosuke, Okumura Kenji, Murohara Toyoaki, Kuzuya Masafumi

CIRCULATION 128 巻 ( 22 ) 2013年11月

HMG-CoA Reductase Inhibitor Pitavastatin Enhances Renoprotective Effects of Angiotensin Receptor1 Blocker Olmesartan In Salt-Sensitive Hypertensive Rats

Inoue Aiko, Cheng Xian Wu, Sasaki Takeshi, Hu Lina, Jang Haiying, Xiang Li, Kuzuya Masafumi, Murohara Toyoaki, Okumura Kenji

CIRCULATION 128 巻 ( 22 ) 2013年11月

Akt is essential for adaptive response of systolic left-ventricular function and aging-induced intolerance to exercise

Aoyama M., Bando Y. Kureishi, Monji A., Cheng X. W., Inoue A., Monji A., Mitsui T., Kuzuya M., Murohara T.

EUROPEAN HEART JOURNAL 34 巻頁： 927 - 927 2013年8月

Mechanisms Underlying the Impairment of Ischemia-Induced Neovascularization in Cathepsin K-Deficient Mic

Jiang Haiying, Cheng Xian Wu, Shi Guo-Ping, Hu Lina, Song Haizhen, Inoue Aiko, Koike Teruhiko, Kuzuya Masafumi

CIRCULATION 126 巻 ( 21 ) 2012年11月

Statins Enhance the Beneficial Effects of Olmesartan on Renal Injury in Salt-Sensitive Hypertensive Rats via the Reduction of an Angiotensin-Mineralocorticoid Receptor Signaling Interaction

Cheng Xian Wu, Inoue Aiko, Hu Lina, Song Haizhen, Sasaki Takeshi, Kuzuya Masafumi, Okumura Kenji, Murohara Toyoaki

CIRCULATION 124 巻 ( 21 ) 2011年11月

Cheng Xian Wu, Song Haizhen, Sasaki Takeshi, Hu Lina, Inoue Aiko, Bando Yasuko K., Shi Guo-Ping, Kuzuya Masafumi, Okumura Kenji, Murohara Toyoaki

HYPERTENSION 57 巻 ( 5 ) 頁： 981 - U238 2011年5月

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

Inhibition of mineralocorticoid receptor is a renoprotective effect of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin

Cheng Xian Wu, Kuzuya Masafumi, Sasaki Takeshi, Inoue Aiko, Hu Lina, Song Haizhen, Huang Zhe, Li Ping, Takeshita Kyosuke, Hirashiki Akihiro, Sato Kohji, Shi Guo-Ping, Okumura Kenji, Murohara Toyoaki

JOURNAL OF HYPERTENSION 29 巻 ( 3 ) 頁： 542 - 552 2011年3月

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

Matrix metalloproteinase-2 regulates the expression of tissue inhibitor of matrix metalloproteinase-2

Statin Inhibits Apoptosis of Vascular Smooth Muscle Cells in Atherogenic Plaque via eNOs/HIF-1 alpha-Mediated IAP-2 Activation: Implication for Plaque Stability

Cheng Xian Wu, Song Haizhen, Hu Lina, Inoue Aiko, Kuzuya Masfumi, Nakamura Kae, Kim Weon, Shi Guo-Ping, Okumura Kenji, Murohara Toyoaki

CIRCULATION 122 巻 ( 21 ) 2010年11月

Superoxide-Dependent Cathepsin Activation is Associated with Hypertensive Renal Remodeling and Dysfunction and Represents a Target for Angiotensin Type 1 Receptor Blocker

Cheng Xian Wu, Sasaki Takeshi, Song Haizhen, Inoue Aiko, Fan Janglin, Hirashiki Akihiro, Shi Guo-Ping, Okumura Kenji, Kuzuya Masafumi, Murohara Toyoaki

CIRCULATION 122 巻 ( 21 ) 2010年11月

Kimura Kaoru, Cheng Xian Wu, Nakamura Kae, Inoue Aiko, Hu Lina, Song Haizhen, Okumura Kenji, Iguchi Akihisa, Murohara Toyoaki, Kuzuya Masafumi

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY 37 巻 ( 11 ) 頁： 1096 - 1101 2010年11月

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

Exercise Training Stimulates Ischemia-Induced Neovascularization via Phosphatidylinositol 3-Kinase/Akt-Dependent Hypoxia-Induced Factor-1 alpha Reactivation in Mice of Advanced Age

Mechanisms Underlying the Exercise Training-Induced Improvement of Neovascularization in Response to Ischemia in Advanced Age

Cheng Xian Wu, Okumura Kenji, Hu Lina, Song Haizhen, Inoue Aiko, Kuzuya Masafumi, Murohara Toyoaki

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 30 巻 ( 11 ) 頁： E247 - E247 2010年11月

Statin-Induced Prevention of Hypertensive Renal Insufficiency Through Reduction of Local Angiotensin Synthesis and NADPH Oxidase-Dependent Activation of the Mineralocorticoid Receptor

Cheng Xian Wu, Okumura Kenji, Inoue Aiko, Hu Lina, Song Haizhen, Sasaki Takeshi, Kuzuya Masafumi, Murohara Toyoaki

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 30 巻 ( 11 ) 頁： E232 - E232 2010年11月

Cheng Xian Wu, Kuzuya Masafumi, Kim Weon, Song Haizhen, Hu Lina, Inoue Aiko, Nakamura Kae, Di Qun, Sasaki Takeshi, Tsuzuki Michitaka, Shi Guo-Ping, Okumura Kenji, Murohara Toyoaki

CIRCULATION 122 巻 ( 7 ) 頁： 707 - 716 2010年8月

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

Angiogenic activity of bFGF and VEGF suppressed by proteolytic cleavage by neutrophil elastase

Exercise Training Stimulates Neovascularization in Response to Ischemia via HIF-1 alpha-VEGF-mediated Activation of MMP-2 in Advanced Age

Cheng Xian Wu, Kuzuya Masafumi, Hu Lina, Kim Weon, Song Haizhen, Inoue Aiko, Shi Guo-Ping, Okumura Kenji, Murohara Toyoaki

CIRCULATION 120 巻 ( 18 ) 頁： S532 - S532 2009年11月

TREATMENT OF APO E-DEFICIENT MICE WITH STATIN INHIBITS THE OXIDATIVE STRESS-DEPENDENT LYSOSMAL PROTEASE CATHEPSIN ACTIVATION SYSTEM: IMPLICATION FOR PLAQUE STABILITY

Cheng X. W., Kuuzya M., Sasaki T., Nakamura K., Song H., Hu L., Inoue A., Shi G-P, Murohara T., Okumura K.

ATHEROSCLEROSIS SUPPLEMENTS 10 巻 ( 2 ) 2009年6月

Treatment of ApoE-Deficient Mice with Statin Inhibits the Oxidative Stress-Dependent Lysosomal Protease Cathepsin Activation System: Implication for Plaque Stability

Cheng Xian Wu, Kuzuya Masafumi, Okumura Kenjl, Nakamura Kae, Inoue Aiko, Sasaki Takeshi, Song Haizhen, Takeshita Kyosuke, Kim Weon, Shi Guo-Ping, Murohara Toyoaki

CIRCULATION 118 巻 ( 18 ) 頁： S559 - S559 2008年10月

Ai Shingo, Cheng Xian Wu, Inoue Aiko, Nakamura Kae, Okumura Kenji, Iguchi Akihisa, Murohara Toyoaki, Kuzuya Masafumi

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 364 巻 ( 2 ) 頁： 395 - 401 2007年12月

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