九州大学-研究者情報 [牧盾 (講師) 九州大学病院集中治療部]

Jun Maki, Mayumi Hirano, Sumio Hoka, Hideo Kanaide, Katsuya Hirano, Involvement of reactive oxygen species in thrombin-induced pulmonary vasoconstriction., American journal of respiratory and critical care medicine, 10.1164/rccm.201002-0255OC, 182, 11, 1435-44, 2010.12, RATIONALE: Pulmonary vascular thrombosis and thrombotic arteriopathy are common pathological findings in pulmonary arterial hypertension. Thrombin may thus play an important role in the pathogenesis and pathophysiology of pulmonary arterial hypertension. OBJECTIVES: The present study aimed to elucidate the contractile effect of thrombin in the pulmonary artery and clarify its underlying mechanisms. METHODS: The changes in cytosolic Ca²(+) concentrations ([Ca²(+)](i)), 20-kD myosin light chain (MLC20) phosphorylation, and contraction were monitored in the isolated porcine pulmonary artery. The production of reactive oxygen species (ROS) was evaluated by fluorescence imaging. MEASUREMENTS AND MAIN RESULTS: In the presence of extracellular Ca²(+), thrombin induced a sustained contraction accompanied by an increase in [Ca²(+)](i) and the phosphorylation of MLC20. In the absence of extracellular Ca²(+), thrombin induced a contraction without either [Ca²(+)](i) elevation or MLC20 phosphorylation. This Ca²(+)- and MLC20 phosphorylation-independent contraction was mimicked by hydrogen peroxide and inhibited by N-acetyl cysteine. Fluorescence imaging revealed thrombin to induce the production of ROS. A Rho-kinase inhibitor, Y27632, inhibited not only the thrombin-induced Ca²(+)- and MLC20 phosphorylation-dependent contraction, but also the Ca²(+)- and MLC20 phosphorylation-independent contraction and the ROS production. These effects of thrombin were mimicked by a proteinase-activated receptor 1 (PAR₁)-activating peptide. CONCLUSIONS: This study elucidated the Ca²(+)- and MLC20 phosphorylation-independent ROS-mediated noncanonical mechanism as well as Ca²(+)- and MLC20 phosphorylation-dependent canonical mechanism that are involved in the thrombin-induced PAR₁-mediated pulmonary vasoconstriction. Rho-kinase was suggested to play multiple roles in the development of thrombin-induced pulmonary vasoconstriction..

Jun Maki, Mayumi Hirano, Sumio Hoka, Hideo Kanaide, Katsuya Hirano, Thrombin activation of proteinase-activated receptor 1 potentiates the myofilament Ca2+ sensitivity and induces vasoconstriction in porcine pulmonary arteries., British journal of pharmacology, 10.1111/j.1476-5381.2009.00591.x, 159, 4, 919-27, 2010.02, BACKGROUND AND PURPOSE: Thrombus formation is commonly associated with pulmonary arterial hypertension (PAH). Thrombin may thus play an important role in the pathogenesis and pathophysiology of PAH. Hence, we investigated the contractile effects of thrombin and its mechanism in pulmonary artery. EXPERIMENTAL APPROACH: The cytosolic Ca(2+) concentrations ([Ca(2+)](i)), 20 kDa myosin light chain (MLC20) phosphorylation and tension development were evaluated using the isolated porcine pulmonary artery. KEY RESULTS: Thrombin induced a sustained contraction in endothelium-denuded strips obtained from different sites of a pulmonary artery, ranging from the main pulmonary artery to the intrapulmonary artery. In the presence of endothelium, thrombin induced a transient relaxation. The contractile effect of thrombin was abolished by either a protease inhibitor or a proteinase-activated receptor 1 (PAR(1)) antagonist, while it was mimicked by PAR(1)-activating peptide (PAR(1)AP), but not PAR(4)AP. The thrombin-induced contraction was associated with a small elevation of [Ca(2+)](i) and an increase in MLC20 phosphorylation. Thrombin and PAR(1)AP induced a greater increase in tension for a given [Ca(2+)](i) elevation than that obtained with high K(+)-depolarization. They also induced a contraction at a fixed Ca(2+) concentration in alpha-toxin-permeabilized preparations. CONCLUSIONS AND IMPLICATIONS: The present study revealed a unique property of the pulmonary artery. In contrast to normal arteries of the systemic circulation, thrombin induces a sustained contraction in the normal pulmonary artery, by activating PAR(1) and thereby increasing the sensitivity of the myofilament to Ca(2+). This responsiveness of the pulmonary artery to thrombin may therefore contribute to the pathogenesis and pathophysiology of PAH..

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主要学会発表等

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Jun Maki, Asami Ikeda, Tsukasa Shimauchi, Kentaro Tokuda , Yuji Karashima, Posterior Reversible Encephalopathy Syndrome Diagnosed After Post Caesarian Section Atonic Hemorrhage, Anesthesiology 2018, 2018.10, A 39 years old primipara underwent a caesarian section because of arrested labor. After delivery, she suffered from atonic hemorrhage and needed massive blood transfusion. In the ICU, Nicardipine was administered to treat hypertension. After extubation, she complained of visual abnormality. MRI finding showed T2-FLAIR hyperintensities in bilateral occipital lobes, suggesting posterior reversible encephalopathy syndrome (PRES). Her blood pressure was tightly controlled, and visual abnormality was improved in a week.Although PRES associated with hypertensive disorder of pregnancy has been reported, PRES developed in perioperative period is rare and difficult to recognize..

学会活動

所属学会名

米国麻酔科学会

米国集中治療学会

日本麻酔科学会

日本集中治療医学会

日本救急医学会

学会大会・会議・シンポジウム等における役割

2015.10.09～2015.10.11, 日本心臓血管麻酔学会　第20回学術集会, シンポジスト.

2014.09.22～2014.09.23, 日本小児麻酔学会　第20回大会, 教育講演の演者.

学術論文等の審査

年度	外国語雑誌査読論文数	日本語雑誌査読論文数	国内会議録査読論文数	合計
2021年度	1	1		2
2020年度	4	2	1	7
2019年度	2			2
2017年度	2			2
2016年度	1			1

その他の研究活動

海外渡航状況, 海外での教育研究歴

カリフォルニア大学サンフランシスコ校, UnitedStatesofAmerica, 2015.03～2015.03.

研究資金

科学研究費補助金の採択状況(文部科学省、日本学術振興会)

2022年度～2026年度, 基盤研究(C), 代表, 敗血症における急性腎障害の発症と慢性腎臓病への進展に関わるメカニズムの解明.

2016年度～2018年度, 基盤研究(C), 代表, 肺高血圧症の新規治療薬としてのトロンビン受容体拮抗薬の可能性.

九大関連コンテンツ

pure2017年10月2日から、「九州大学研究者情報」を補完するデータベースとして、Elsevier社の「Pure」による研究業績の公開を開始しました。

QIR　九州大学学術情報リポジトリシステム情報科学研究院

九州大学病院


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