研究者詳細 - 竹藤　幹人

Assessment of In-Stent Restenosis Using High-Definition Computed Tomography With a New Gemstone Detector.

Tsuda T, Ishii H, Ichimiya S, Kanashiro M, Watanabe J, Takefuji M, Aoyama T, Suzuki S, Tanaka A, Matsubara T, Murohara T

Circulation journal : official journal of the Japanese Circulation Society 79 巻 ( 7 ) 頁： 1542 - 8 2015年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本循環器学会

Background: Until now, there have been few reports on the accuracy of in-stent restenosis (ISR) detection using high-definition computed tomography (HDCT). The purpose of this study was to assess ISR using HDCT with a new gemstone detector and to examine the diagnostic accuracy compared with invasive coronary angiography. Methods and Results: We evaluated 162 consecutive patients with 316 stents and the image quality (IQ) scores used to assess ISR, and analyzed whether stent strut thickness and diameter affected IQ score and assessability. In the 316 stents, 278 were diagnosed as assessable with HDCT (88.0%). IQ score for stent diameter ≥3 mm was significantly higher than that for stent diameter <3 mm, for stents with both thick struts ≥140 μm in thickness (mean IQ: 2.04±0.97 vs. 2.83±1.06, P<0.001) and thin struts <140 μm (mean IQ: 1.92±0.87 vs. 2.64±0.96, P=0.01). Assessability for stent diameter ≥3 mm was significantly higher than that for stent diameter <3 mm only for stents with thick struts (92.8% vs. 76.1%, P<0.001). Stent strut thickness, however, was not statistically significantly associated with either IQ score or assessability. Conclusions: In-stent lumens have high HDCT assessability, and HDCT is useful to evaluate thick-strut stents with diameter <3 mm.

DOI： 10.1253/circj.CJ-14-1344

Akt-dependent Girdin phosphorylation regulates repair processes after acute myocardial infarction. 査読有り

Hayano S, Takefuji M, Maeda K, Noda T, Ichimiya H, Kobayashi K, Enomoto A, Asai N, Takahashi M, Murohara T

J Mol Cell Cardiol. 88 巻頁： 55-63 2015年

RhoGEF-mediated vasoconstriction in hypertension.

Takefuji M, Yura Y, Kaibuchi K, Murohara T

Hypertension research : official journal of the Japanese Society of Hypertension 36 巻 ( 11 ) 頁： 930 - 1 2013年11月

G13 controls angiogenesis through regulation of VEGFR-2 expression.

Sivaraj KK, Takefuji M, Schmidt I, Adams RH, Offermanns S, Wettschureck N

Developmental cell 25 巻 ( 4 ) 頁： 427 - 34 2013年5月

RhoGEF12 controls cardiac remodeling by integrating G protein- and integrin-dependent signaling cascades.

Takefuji M, Krüger M, Sivaraj KK, Kaibuchi K, Offermanns S, Wettschureck N

The Journal of experimental medicine 210 巻 ( 4 ) 頁： 665 - 73 2013年4月

記述言語：英語出版者・発行元：Journal of Experimental Medicine

Structural cardiac remodeling, including hypertrophy and fibrosis, plays a crucial role in the pathogenesis of heart failure. In vitro studies suggested a role of the small GTPase RhoA in hypertrophic cardiomyocyte growth, but neither the molecular mechanisms leading to RhoA activation nor their relevance in vivo are known. We use here a mass spectrometric approach to identify Rho guanine nucleotide exchange factors (RhoGEFs) activated during cardiac pressure overload in vivo and show that RhoGEF12 is a central player during cardiac remodeling. We show that RhoGEF12 is required for stretch-induced RhoA activation and hypertrophic gene transcription in vitro and that its activation depends on integrin β1 and heterotrimeric G proteins of the G12/13 family. In vivo, cardiomyocyte-specific deletion of RhoGEF12 protects mice from overload-induced hypertrophy, fibrosis, and development of heart failure. Importantly, in mice with preexisting hypertrophy, induction of RhoGEF12 deficiency protects from cardiac decompensation, resulting in significantly increased longterm survival. Collectively, RhoGEF12 acts as an integrator of stretch-induced signaling cascades in cardiomyocytes and is an interesting new target for therapeutic intervention in patients with pressure overload-induced heart failure. © 2013 Takefuji et al.

DOI： 10.1084/jem.20122126

Mutation of ARHGAP9 in patients with coronary spastic angina.

RhoGEF-mediated vasoconstriction in hypertension 査読有り

Takefuji M, Yura Y, Kaibuchi K, Murohara T

Hypertens Res. 36 巻 ( 11 ) 頁： 930-931 2013年

RhoGEF12 controls cardiac remodeling by intergrating G protein- and integrin-dependent signaling cascades. 査読有り

Takefuji M, Kruger M, Sivaraj KK, Kaibuchi K, Offermanns S, Wettshureck N

J Exp Med. 210 巻 ( 4 ) 頁： 665-673 2013年

G13 controls angiogenesis through regulation of VEGFR-2 expression 査読有り

Sivaraj KK, Takefuji M, Schmidt I, Adams RH, Offermanns S, Wettchureck N

Dev Cell 25 巻 ( 4 ) 頁： 427-434 2013年

RhoGEF-mediated vasoconstriction in hypertension 査読有り

Takefuji M, Yura Y, Kaibuchi K, Murohara T

Hypertens Res. 36 巻 ( 11 ) 頁： 930-931 2013年

Procontractile G protein-mediated signaling pathways antagonistically regulate smooth muscle differentiation in vascular remodeling.

Althoff TF, Albarrán Juárez J, Troidl K, Tang C, Wang S, Wirth A, Takefuji M, Wettschureck N, Offermanns S

The Journal of experimental medicine 209 巻 ( 12 ) 頁： 2277 - 90 2012年11月

G(13)-mediated signaling pathway is required for pressure overload-induced cardiac remodeling and heart failure.

Takefuji M, Wirth A, Lukasova M, Takefuji S, Boettger T, Braun T, Althoff T, Offermanns S, Wettschureck N

Circulation 126 巻 ( 16 ) 頁： 1972 - 82 2012年10月

Procontractile G protein-mediated signaling pathways antagonistically regulate smooth muscle differentiation in vascular remodeling. 査読有り

Althoff TF, Juarez JA, Troidl K, Wirth A, Takefuji M, Wettschureck N

J Exp Med. 209 巻 ( 12 ) 頁： 2277-2290 2012年

G(13)-mediated signaling pathway is required for pressure overload-induced cardiac remodeling and heart failure. 査読有り

Takefuji M, Wirth A, Lukasova M, Takefuji S, Boettger T, Braun T, Althoff T, Offermanns S, Wettschureck N

Circulation 126 巻 ( 16 ) 頁： 1972-1982 2012年

Takefuji M, Asano H, Mori K, Amano M, Kato K, Watanabe T, Morita Y, Katsumi A, Itoh T, Takenawa T, Hirashiki A, Izawa H, Nagata K, Hirayama H, Takatsu F, Naoe T, Yokota M, Kaibuchi K

Journal of human genetics 55 巻 ( 1 ) 頁： 42 - 9 2010年1月

記述言語：英語出版者・発行元：Journal of Human Genetics

Coronary artery spasm has an important function in the etiology of variant angina and other acute coronary syndromes. Abnormal activation of Rho-family GTPases has been observed in cardiovascular disorders, but the function of genetic variability in Rho-family GTPases remains to be evaluated in cardiovascular disorders. We examined the genetic variability of Rho-family GTPases and their regulators in coronary artery spasm. We performed a comprehensive candidate gene analysis of 67 single nucleotide polymorphisms with amino-acid substitution in Rho-family GTPases and their regulators in 103 unrelated Japanese patients with acetylcholine-induced coronary artery spasm and 102 control Japanese subjects without acetylcholine-induced coronary artery spasm. We noted an association of the single nucleotide polymorphism of ARHGAP9 (rs11544238, Ala370Ser) with coronary artery spasm (odds ratio=2.67). We found that ARHGAP9 inactivated Rac as RacGAP and that the mRNA level of ARHGAP9 was strongly detected in hematopoietic cells. ARHGAP9 negatively regulated cell migration. The Ala370Ser polymorphism counteracted ARHGAP9-reduced cell migration, spreading and adhesion. The Ala370Ser polymorphism in the ARHGAP9 gene is associated with coronary artery spasm. These data suggest that the polymorphism of ARHGAP9 has a critical function in the infiltration of hematopoietic cells into the endothelium and inflammation leading to endothelial dysfunction. © 2010 The Japan Society of Human Genetics. All rights reserved.

DOI： 10.1038/jhg.2009.120

Mutation of ARHGAP9 in patients with coronary spastic angina 査読有り

Takefuji M, Asano H, Mori K, Amano M, Kato K, Watanabe T, Morita Y, Katsumi A, Takenawa T, Hirashiki A, Nagata K, Hirayama H, Takatsu F, Naoe T, Kaibuchi K

J Hum Genet. 55 巻 ( 1 ) 頁： 42-49 2010年

Rho-kinase contributes to sustained RhoA activation through phosphorylation of p190A RhoGAP. 査読有り

Mori K, Amano M, Takefuji M, Kato K, Morita Y, Nishioka T, Matsuura Y, Murohara T, Kaibuchi K

The Journal of biological chemistry 284 巻 ( 8 ) 頁： 5067 - 76 2009年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biological Chemistry

RhoA is transiently activated by specific extracellular signals such as endothelin-1 (ET-1) in vascular smooth muscle cells. RhoGAP negatively regulates RhoA activity: thus, RhoA becomes the GDP-bound inactive form afterward. Sustained activation of RhoA is induced with high doses of the extracellular signals and is implicated in certain diseases such as vasospasms. However, it remains largely unknown how prolonged activation of RhoA is induced. Here we show that Rho-kinase, an effector of RhoA, phosphorylated p190A RhoGAP at Ser1150 and attenuated p190A RhoGAP activity in COS7 cells. Binding of Rnd to p190A RhoGAP is thought to enhance its activation. Phosphorylation of p190A RhoGAP by Rho-kinase impaired Rnd binding. Stimulation of vascular smooth muscle cells with a high dose of ET-1 provoked sustained RhoA activation and p190A RhoGAP phosphorylation, both of which were prohibited by a Rho-kinase inhibitor. The phosphomimic mutation of p190A RhoGAP weakened Rnd binding and RhoGAP activities. Taken together, these results suggest that ET-1 induces Rhokinase activation and subsequent phosphorylation of p190A RhoGAP, leading to prolonged RhoA activation. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI： 10.1074/jbc.M806853200