研究者詳細 - 杉本　昌之

論文 - 杉本　昌之

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Rho-Kinase Phosphorylates PAR-3 and Disrupts PAR Complex Formation

Nakayama M., Goto T.M., Sugimoto M., Nishimura T., Shinagawa T., Ohno S., Amano M., Kaibuchi K.

Developmental Cell 14 巻 ( 2 ) 頁： 205 - 215 2008年2月

記述言語：英語出版者・発行元：Developmental Cell

A polarity complex of PAR-3, PAR-6, and atypical protein kinase C (aPKC) functions in various cell polarization events. PAR-3 directly interacts with Tiam1/Taim2 (STEF), Rac1-specific guanine nucleotide exchange factors, and forms a complex with aPKC-PAR-6-Cdc42•GTP, leading to Rac1 activation. RhoA antagonizes Rac1 in certain types of cells. However, the relationship between RhoA and the PAR complex remains elusive. We found here that Rho-kinase/ROCK/ROK, the effector of RhoA, phosphorylated PAR-3 at Thr833 and thereby disrupted its interaction with aPKC and PAR-6, but not with Tiam2. Phosphorylated PAR-3 was observed in the leading edge, and in central and rear portions of migrating cells having front-rear polarity. Knockdown of PAR-3 by small interfering RNA (siRNA) impaired cell migration, front-rear polarization, and PAR-3-mediated Rac1 activation, which were recovered with siRNA-resistant PAR-3, but not with the phospho-mimic PAR-3 mutant. We propose that RhoA/Rho-kinase inhibits PAR complex formation through PAR-3 phosphorylation, resulting in Rac1 inactivation. © 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.devcel.2007.11.021

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Rho-kinase phosphorylates eNOS at threonine 495 in endothelial cells

Sugimoto M., Nakayama M., Goto T.M., Amano M., Komori K., Kaibuchi K.

Biochemical and Biophysical Research Communications 361 巻 ( 2 ) 頁： 462 - 467 2007年9月

記述言語：英語出版者・発行元：Biochemical and Biophysical Research Communications

Endothelial nitric oxide synthase (eNOS) produces nitric oxide (NO), which is involved in various physiological functions of the cardiovascular system. eNOS is activated by dephosphorylation at Thr495 and phosphorylation at Ser1177. Inhibition of Rho-kinase, an effector of the small GTPase RhoA, leads to activation of Akt/PKB, which phosphorylates eNOS at Ser1177 and thereby promotes NO production. However, little is known about the effects of Rho-kinase on phosphorylation of Thr495. We here found that the constitutively active form of Rho-kinase phosphorylated eNOS at Thr495 in vitro. Expression of the constitutively active form of RhoA or Rho-kinase increased this phosphorylation in COS-7 cells. Addition of thrombin to cultured human umbilical vein endothelial cells induced phosphorylation of eNOS at Thr495. Treatment with Y27632, a Rho-kinase inhibitor, suppressed thrombin-induced phosphorylation at Thr495. These results indicate that Rho-kinase can directly phosphorylate eNOS at Thr495 to suppress NO production in endothelium. © 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.07.030

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Rho-kinase phosphorylates PAR-3 and regulates cell polarity.

Nakayama, M; Goto, T; Sugimoto, M; Nishimura, T; Hoshino, M; Ohno, S; Amano, M; Kaibuchi, K

JOURNAL OF PHARMACOLOGICAL SCIENCES 103 巻頁： 50P - 50P 2007年

Identification of Par3asa novel substrate of Rho-kinase

Nakayama, M; Nishimura, T; Sugimoto, M; Goto, T; Ohno, S; Amano, M; Kaibuchi, K

JOURNAL OF PHARMACOLOGICAL SCIENCES 100 巻頁： 182P - 182P 2006年

Rho-kinase phosphorylates eNOS at Thr495 in vascular endothelial cells, and inactivates it

Sugimoto, M; Nakayama, M; Goto, T; Amano, M; Komori, K; Kaibuchi, K

JOURNAL OF PHARMACOLOGICAL SCIENCES 100 巻頁： 278P - 278P 2006年

Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition

Yamanouchi D., Banno H., Nakayama M., Sugimoto M., Fujita H., Kobayashi M., Kuwano H., Komori K.

Journal of Vascular Surgery 42 巻 ( 4 ) 頁： 757 - 764 2005年10月

記述言語：英語出版者・発行元：Journal of Vascular Surgery

Background: Recent studies suggest that statins can protect the vasculature in a manner that is independent of their lipid-lowering activity through inhibition of the small guanosine triphosphate-binding protein, Rho, and Rho-associated kinase. Little information is available on the inhibitory effect of statins on vein graft intimal hyperplasia, the main cause of late graft failure after bypass grafting. We therefore examined the effects of a hydrophilic statin on vein graft intimal hyperplasia in vivo and Rho-kinase activity in vitro. Methods: In the first experiment, rabbits were randomized to a control group (n = 7) that was fed regular rabbit chow or to a pravastatin group (n = 7) that was fed regular rabbit chow supplemented with 10 mg/kg pravastatin sodium. The branches of the jugular vein were ligated and an approximately 3-cm segment of the jugular vein was taken for an autologous reversed-vein graft. The carotid artery was cut and replaced with the harvested autologous jugular vein. At 2 and 4 weeks after the operation, vein grafts in both groups were harvested, and intimal hyperplasia of the vein grafts was assessed. In the second experiment, human umbilical vein endothelial cells and vascular smooth muscle cells were cultured and then treated with 1 μmol/L and 30 μmol/L pravastatin for 24 hours and harvested. Immunoblotting was performed on the resulting precipitates. Quantitative evaluation of phosphorylated myosin binding subunit and endothelial nitric oxide synthase was performed by densitometric analysis. Results: We demonstrated that oral administration of the hydrophilic statin pravastatin to normocholesterolemic rabbits inhibited intimal hyperplasia of carotid interposition-reversed jugular vein grafts 4 weeks after implantation (pravastatin group, 39.5 ± 3.5 μm vs control group, 64.0 ± 7.1 μm; n = 7; P < .05) and suppressed cell proliferation and apoptosis in the neointima 2 weeks after implantation. In addition, we found that pravastatin inhibited Rho-kinase activity and accelerated endothelial nitric oxide synthase expression in human umbilical vein endothelial cells but did not inhibit Rho-kinase activity in vascular smooth muscle cells. Conclusions: These novel findings clearly demonstrate that a hydrophilic statin can suppress intimal hyperplasia of the vein graft in vivo and also show endothelial cell-tropic inhibition of Rho-kinase in vitro. Furthermore, these results strongly support the clinical use of hydrophilic statins to prevent intimal hyperplasia of the vein graft after bypass grafting. Clinical Relevance: Late graft failure caused by neointimal hyperplasia limits the efficacy of vein grafting. Various treatments were examined to reduce neointimal hyperplasia, but a standard clinical treatment has not yet been established. We report here the inhibitory effect of pravastatin on the development of vein graft intimal hyperplasia. In addition, we demonstrate that pravastatin showed endothelial cell-tropic benefits through both the inhibition of Rho-kinase activity and acceleration of eNOS expression in vitro. Because the clinical benefits and safety of pravastatin have been established to a certain extent through long-term clinical usage, pravastatin may soon become standard treatment after vein bypass grafting. Copyright © 2005 by The Society for Vascular Surgery.

DOI： 10.1016/j.jvs.2005.05.041

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Buerger’s disease (thromboangiitis obliterans)

Sugimoto M.

Systemic Vasculitides: Current Status and Perspectives 頁： 361 - 376 2016年1月

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