研究者詳細 - 王　英正

MISC - 王　英正

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Deficiency of Nectin-2 Leads to Cardiac Fibrosis and Dysfunction Under Chronic Pressure Overload

Seimi Satomi-Kobayashi, Tomomi Ueyama, Steffen Mueller, Ryuji Toh, Tomoya Masano, Tsuyoshi Sakoda, Yoshiyuki Rikitake, Jun Miyoshi, Hiroaki Matsubara, Hidemasa Oh, Seinosuke Kawashima, Ken-ichi Hirata, Yoshimi Takai

HYPERTENSION 54 ( 4 ) 825 - U268 2009年10月

記述言語：英語出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

The intercalated disc, a cell-cell contact site between neighboring cardiac myocytes, plays an important role in maintaining the homeostasis of the heart by transmitting electric and mechanical signals. Changes in the architecture of the intercalated disc have been observed in dilated cardiomyopathy. Among cell-cell junctions in the intercalated disc, adherens junctions are involved in anchoring myofibrils and transmitting force. Nectins are Ca(2+)-independent, immunoglobulin-like cell-cell adhesion molecules that exist in adherens junctions. However, the role of nectins in cardiac homeostasis and integrity of the intercalated disc are unknown. Among the isoforms of nectins, nectin-2 and -4 were expressed at the intercalated disc in the heart. Nectin-2-knockout mice showed normal cardiac structure and function under physiological conditions. Four weeks after banding of the ascending aorta, cardiac function was significantly impaired in nectin-2-knockout mice compared with wild-type mice, although both nectin-2-knockout and wild-type mice developed similar degrees of cardiac hypertrophy. Banded nectin-2-knockout mice displayed cardiac fibrosis more evidently than banded wild-type mice. The disruption of the intercalated discs and disorganized myofibrils were observed in banded nectin-2-knockout mice. Furthermore, the number of apoptotic cardiac myocytes was increased in banded nectin-2-knockout mice. In the hearts of banded nectin-2-knockout mice, Akt remained at lower phosphorylation levels until 2 weeks after banding, whereas c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were highly phosphorylated compared with those of wild-type mice. These results indicate that nectin-2 is required to maintain structure and function of the intercalated disc and protects the heart from pressure-overload induced cardiac dysfunction. (Hypertension. 2009; 54: 825-831.)

DOI： 10.1161/HYPERTENSIONAHA.109.130443

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5 Cardiac Regenerative Hybrid-therapy Integrated via Human Autologous Cardiac Stem Cell and Biodegradable bFGF-incorporating Gelatin Hydrogel(Therapeutic Strategy for Severe Heart Failure-From LVAD to Heart Transplantation-,Symposium 11 (SY-11) (H),The 73rd Annual Scientific Meeting of The Japanese Circulation Society)

Takehara Naofumi, Tsutsumi Yoshiaki, Amano Katsuya, Takahashi Tomosaburo, Yaku Hitoshi, Tabata Yasuhiko, Oh Hidemasa, Hasebe Naoyuki, Matsubara Hiroaki

Circulation journal : official journal of the Japanese Circulation Society 73 43 - 43 2009年3月

Cardiosphereを用いた心筋再生医療

中西直彦, 竹原有史, 中岡幹彦, 赤壁佳樹, 王英正, 松原弘明

総合臨床 2009年

ヒト心臓由来幹細胞を用いた心不全への再生医療

小出正洋, 星野温, 山口真一郎, 岸田聡, 竹原有史, 王英正, 松原弘明

再生誘導治療 2009年

心筋幹細胞

王英正

循環器科特集 2009年

重症心不全に対する細胞治療法

竹原有史, 塘義明, 天野克也, 王英正, 長谷部直幸, 松原弘明

循環器科特集 2009年

Cardiosphereを用いた心筋再生医療

中岡幹彦, 竹原有史, 中西直彦, 赤壁佳樹, 王英正, 松原弘明

再生医療 2009年

自己心臓幹細胞を用いた心不全への細胞治療

岸田聡, 竹原有史, 王英正, 松原弘明

重症心不全の予防と治療 2009年

新しい心臓再生法

王英正

Medical View Point 2009年

Cardiosphereによる心筋再生

竹原有史, 服部玲治, 松原弘明, 王英正

Annual Review 循環器 2009年

Cardiosphereによる心筋再生医療

山口真一郎, 竹原有史, 天野克也, 高橋知三郎, 王英正, 松原弘明

分子心血管病特集 2009年

新規心筋細胞特異的膜蛋白PARM-1は,心筋細胞においてERストレス誘導性でありアポトーシスに対して抑制的に働いている

五十殿弘二, 五十殿弘二, 高橋知三郎, 高橋知三郎, 井本裕子, 井本裕子, 小形岳寛, 浅田聡, 浅田聡, 足立敦郎, 足立敦郎, 上山知巳, 上山知巳, 王英正, 松原弘明, 松原弘明

日本高血圧学会総会プログラム・抄録集 32nd 2009年

Downregulation of Dicer expression by serum withdrawal sensitizes human endothelial cells to apoptosis

Satoshi Asada, Tomosaburo Takahashi, Koji Isodono, Atsuo Adachi, Hiroko Imoto, Takehiro Ogata, Tomomi Ueyama, Hiroaki Matsubara, Hidemasa Oh

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 295 ( 6 ) H2512 - H2521 2008年12月

記述言語：英語出版者・発行元：AMER PHYSIOLOGICAL SOC

Downregulation of Dicer expression by serum withdrawal sensitizes human endothelial cells to apoptosis. Am J Physiol Heart Circ Physiol 295: H2512-H2521, 2008. First published October 31, 2008; doi:10.1152/ajpheart.00233.2008.-Although the modulated expression of Dicer is documented upon neoplastic transformation, little is known of the regulation of Dicer expression by environmental stimuli and its roles in the regulation of cellular functions in primary cells. In this study, we found that Dicer expression was downregulated upon serum withdrawal in human umbilical vein endothelial cells (HUVECs). Serum withdrawal induced a time-dependent repression of Dicer expression, which was specifically rescued by vascular endothelial cell growth factor or sphingosine-1-phosphate. When Dicer expression was silenced by short-hairpin RNA against Dicer, the cells were more prone to apoptosis under serum withdrawal, whereas the rate of apoptosis was comparable with control cells in the serum-containing condition. Real-time PCR-based gene expression profiling identified several genes, the expression of which was modulated by Dicer silencing, including adhesion and matrix-related molecules, caspase-3, and nitric oxide synthase 3 (NOS3). Dicer silencing markedly impaired migratory functions without affecting cell adhesion and repressed phosphorylation of focal adhesion kinase and proline-rich tyrosine kinase 2 in adherent HUVECs. Dicer knockdown upregulated caspase-3 and downregulated NOS3 expression, and serum withdrawal indeed increased caspase-3 and decreased NOS3 expression. Furthermore, the overexpression of Dicer in HUVECs resulted in a marked reduction in apoptosis upon serum withdrawal and a decreased caspase-3 and increased NOS3 expression. The inhibition of NOS activity by N(omega)-nitro-L-arginine methyl ester abrogated the effect of Dicer overexpression to rescue the cells from serum withdrawal-induced apoptosis. These results indicated that serum withdrawal decreases Dicer expression, leading to an increased susceptibility to apoptosis through the regulation of caspase-3 and NOS3 expression.

DOI： 10.1152/ajpheart.00233.2008

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Stemming heart failure with cardiac- or reprogrammed-stem cells

Kento Tateishi, Naofumi Takehara, Hiroaki Matsubara, Hidemasa Oh

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE 12 ( 6A ) 2217 - 2232 2008年12月

記述言語：英語掲載種別：書評論文，書評，文献紹介等出版者・発行元：WILEY-BLACKWELL

Despite extensive efforts to control myocyte growth by genetic targeting of the cell cycle machinery and small molecules for cardiac repair, adult myocytes themselves appeared to divide a limited number of times in response to a variety of cardiac muscle stresses. Rare tissue-resident stem cells are thought to exist in many adult organs that are capable of self-renewal and differentiation and possess a range of actions that are potentially therapeutic. Recent studies suggest that a population of cardiac stem cells (CSCs) is maintained after cardiac development in the adult heart in mammals including human beings; however, homeostatic cardiomyocyte replacement might be stem cell-dependent, and functional myocardial regeneration after cardiac muscle damage is not yet considered as sufficient to fully maintain or reconstitute the cardiovascular system and function. Although it is clear that adult CSCs have limitations in their capabilities to proliferate extensively and differentiate in response to injury in vivo for replenishing mature car-diomyocytes and potentially function as resident stem cells. Transplantation of CSCs expanded ex vivo seems to require an integrated strategy of cell growth-enhancing factor(s) and tissue engineering technologies to support the donor cell survival and subsequent proliferation and differentiation in the host microenvironment. There has been substantial interest regarding the evidence that mammalian fibroblasts can be genetically reprogrammed to induced pluripotent stem (iPS) cells, which closely resemble embryonic stem (ES) cell properties capable of differentiating into functional cardiomyocytes, and these cells may provide an alternative cell source for generating patient-specific CSCs for therapeutic applications.

DOI： 10.1111/j.1582-4934.2008.00487.x

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Controlled Delivery of Basic Fibroblast Growth Factor Promotes Human Cardiosphere-Derived Cell Engraftment to Enhance Cardiac Repair for Chronic Myocardial Infarction

Naofumi Takehara, Yoshiaki Tsutsumi, Kento Tateishi, Takehiro Ogata, Hideo Tanaka, Tomomi Ueyama, Tomosaburo Takahashi, Tetsuro Takamatsu, Masanori Fukushima, Masashi Komeda, Masaaki Yamagishi, Hitoshi Yaku, Yasuhiko Tabata, Hiroaki Matsubara, Hidemasa Oh

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 52 ( 23 ) 1858 - 1865 2008年12月

記述言語：英語出版者・発行元：ELSEVIER SCIENCE INC

Objectives This study was designed to determine whether controlled release of basic fibroblast growth factor ( bFGF) might improve human cardiosphere-derived cell (hCDC) therapy in a pig model of chronic myocardial infarction.
Background Current cell therapies for cardiac repair are limited by loss of the transplanted cells and poor differentiation.
Methods We conducted 2 randomized, placebo-controlled studies in immunosuppressed pigs with anterior myocardial infarctions. Four weeks after coronary reperfusion, 14 pigs were randomly assigned to receive an intramyocardial injection of placebo medium with or without bFGF-incorporating hydrogel implantation. As a second study, 26 pigs were randomized to receive controlled release of bFGF combined with or without hCDCs or bone marrow-derived mesenchymal stem cell transplantation 4 weeks after reperfusion.
Results Controlled release of bFGF in ischemic myocardium significantly augmented the formation of microvascular networks to enhance myocardial perfusion and contractile function. When combined with cell transplantation, the additive effects of bFGF were confined to hCDC-injected animals, but were not observed in animals receiving human bone marrow-derived mesenchymal stem cell transplantation. This was shown by increased donor-cell engraftment and enhanced cardiomyocyte differentiation in the transplanted hearts, resulting in synergistically improved ventricular function and regional wall motion and reduced infarct size.
Conclusions Controlled delivery of bFGF modulates the post-ischemic microenvironment to enhance hCDC engraftment and differentiation. This novel strategy demonstrates significant functional improvements after myocardial infarction and may potentially represent a therapeutic approach to be studied in a clinical trial in human heart failure. (J Am Coll Cardiol 2008; 52: 1858-65) (c) 2008 by the American College of Cardiology Foundation

DOI： 10.1016/j.jacc.2008.06.052

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Crossveinless-2 controls bone morphogenetic protein signaling during early cardiomyocyte differentiation in P19 cells

Koichiro Harada, Akiko Ogai, Tomosaburo Takahashi, Masafumi Kitakaze, Hiroaki Matsubara, Hidemasa Oh

JOURNAL OF BIOLOGICAL CHEMISTRY 283 ( 39 ) 26705 - 26713 2008年9月

記述言語：英語出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Increasing evidence indicates that bone morphogenetic proteins (BMPs) are crucial for cardiac induction, specification, and development. Although signaling of BMPs is tightly regulated through soluble BMP-binding proteins, how they regulate BMP signaling during cardiac differentiation remains unknown. To identify molecules responsible for BMP signaling during early cardiomyocyte differentiation of P19 cells, cDNA subtraction was performed. We found a bimodal expression of the BMP-binding protein Crossveinless-2 (Cv2) during cardiomyocyte differentiation; Cv2 is temporally expressed earlier than cardiac transcription factors such as Nkx2.5 and Tbx5 and acts as a suppressor for BMP signaling in P19 cells. We established a P19 clonal cell line harboring a cardiac alpha-myosin heavy chain promoter-driven enhanced green fluorescent protein gene to monitor cardiac differentiation by flow cytometry. Treatment with BMP2 during the first 2 days of differentiation suppressed cardiomyocyte differentiation through activation of downstream targets Smad1/5/8 protein and Id1 gene, whereas treatment with Cv2 conversely inhibited Smad1/5/8 activation and Id1 expression, leading to increased generation of cardiac cells. RNA interference-mediated knockdown (KD) of endogenous Cv2 showed increased Smad1/5/8 activation and impaired cardiomyocyte differentiation. Expression of cardiac mesoderm markers was reduced, whereas expression of Id1 and endoderm markers such as Sox7, Hnf4, and E-cadherin was induced in Cv2-kinase dead cells. These phenotypes were rescued by the addition of Cv2 protein to the culture media during the first 2 days of differentiation or co-culture with parental cells. These data suggest that Cv2 may specify cardiac mesodermal lineage through inhibition of BMP signaling at early stage of cardiogenesis.

DOI： 10.1074/jbc.M801485200

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MURC, a muscle-restricted coiled-coil protein, is involved in the regulation of skeletal myogenesis

Masashi Tagawa, Tomomi Ueyama, Takehiro Ogata, Naofumi Takehara, Norio Nakajima, Koji Isodono, Satoshi Asada, Tomosaburo Takahashi, Hiroaki Matsubara, Hidemasa Oh

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY 295 ( 2 ) C490 - C498 2008年8月

記述言語：英語出版者・発行元：AMER PHYSIOLOGICAL SOC

Skeletal myogenesis is a multistep process by which multinucleated mature muscle fibers are formed from undifferentiated, mononucleated myoblasts. However, the molecular mechanisms of skeletal myogenesis have not been fully elucidated. Here, we identified muscle-restricted coiled-coil (MURC) protein as a positive regulator of myogenesis. In skeletal muscle, MURC was localized to the cytoplasm with accumulation in the Z-disc of the sarcomere. In C2C12 myoblasts, MURC expression occurred coincidentally with myogenin expression and preceded sarcomeric myosin expression during differentiation into myotubes. RNA interference (RNAi)-mediated knockdown of MURC impaired differentiation in C2C12 myoblasts, which was accompanied by impaired myogenin expression and ERK activation. Overexpression of MURC in C2C12 myoblasts resulted in the promotion of differentiation with enhanced myogenin expression and ERK activation during differentiation. During injury-induced muscle regeneration, MURC expression increased, and a higher abundance of MURC was observed in immature myofibers compared with mature myofibers. In addition, ERK was activated in regenerating tissue, and ERK activation was detected in MURC-expressing immature myofibers. These findings suggest that MURC is involved in the skeletal myogenesis that results from modulation of myogenin expression and ERK activation. MURC may play pivotal roles in the molecular mechanisms of skeletal myogenic differentiation.

DOI： 10.1152/ajpcell.00188.2008

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PARM-1, a Novel Transmembrane Molecule Involved in Endoplasmic Reticulum Stress-Induced Apoptosis in Cardiac Myocytes

Tomosaburo Takahashi, Koji Isodono, Takehiro Ogata, Satoshi Asada, Hiroko Imoto, Atsuo Adachi, Tomomi Ueyama, Hidemasa Oh, Hiroaki Matsubara

CIRCULATION RESEARCH 103 ( 5 ) E63 - E63 2008年8月

MURC, A Muscle-Restricted Coiled-Coil Protein, Induces Cardiomyocyte Hypertrophy Through the Extracellular Signal-Regulated Kinase Pathway

Takehiro Ogata, Tomomi Ueyama, Koji Isodono, Hiroko Imoto, Masashi Tagawa, Norifumi Takehara, Satoshi Asada, Atsuo Adachi, Tomosaburo Takahashi, Hiroaki Matsubara, Hidemasa Oh

CIRCULATION RESEARCH 103 ( 5 ) E57 - E57 2008年8月

MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance

Takehiro Ogata, Tomomi Ueyama, Koji Isodono, Masashi Tagawa, Naofumi Takehara, Tsuneaki Kawashima, Koichiro Harada, Tomosaburo Takahashi, Tetsuo Shioi, Hiroaki Matsubara, Hidemasa Oh

MOLECULAR AND CELLULAR BIOLOGY 28 ( 10 ) 3424 - 3436 2008年5月

記述言語：英語出版者・発行元：AMER SOC MICROBIOLOGY

We identified a novel muscle-restricted putative coiled-coil protein, MURC, which is evolutionarily conserved from frog to human. MURC was localized to the cytoplasm with accumulation in the Z-line of the sarcomere in the murine adult heart. MURC mRNA expression in the heart increased during the developmental process from the embryonic stage to adulthood. In response to pressure overload, MURC mRNA expression increased in the hypertrophied heart. Using the yeast two-hybrid system, we identified the serum deprivation response (SDPR) protein, a phosphatidylserine-binding protein, as a MURC-binding protein. MURC induced activation of the RhoA/ROCK pathway, which modulated serum response factor-mediated atrial natriuretic peptide (ANP) expression and myofibrillar organization. SDPR augmented MURC-induced transactivation of the ANP promoter in cardiomyocytes, and RNA interference of SDPR attenuated the action of MURC on the ANP promoter. Transgenic mice expressing cardiac-specific MURC (Tg-MURC) exhibited cardiac contractile dysfunction and atrioventricular (AV) conduction disturbances with atrial chamber enlargement, reduced thickness of the ventricular wall, and interstitial fibrosis. Spontaneous episodes of atrial fibrillation and AV block were observed in Tg-MURC mice. These findings indicate that MURC modulates RhoA signaling and that MURC plays an important role in the development of cardiac dysfunction and conduction disturbance with increased vulnerability to atrial arrhythmias.

DOI： 10.1128/MCB.02186-07

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