Thrombin activation of proteinase-activated receptor 1 potentiates the myofilament Ca 2+ sensitivity and induces vasoconstriction in porcine pulmonary arteries

Jun Maki, Mayumi Hirano, Sumio Hoka, Hideo Kanaide, Katsuya Hirano

研究成果: ジャーナルへの寄稿記事

11 引用 (Scopus)

抄録

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 1AP), but not PAR 4AP. The thrombin-induced contraction was associated with a small elevation of Ca 2+ i and an increase in MLC20 phosphorylation. Thrombin and PAR 1AP 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 -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.

元の言語英語
ページ(範囲)919-927
ページ数9
ジャーナルBritish Journal of Pharmacology
159
発行部数4
DOI
出版物ステータス出版済み - 2 1 2010

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PAR-1 Receptor
Myofibrils
Vasoconstriction
Thrombin
Pulmonary Artery
Swine
Pulmonary Hypertension
Endothelium
Arteries
Phosphorylation
Myosin Light Chains
Protease Inhibitors
Thrombosis

All Science Journal Classification (ASJC) codes

  • Pharmacology

これを引用

Thrombin activation of proteinase-activated receptor 1 potentiates the myofilament Ca 2+ sensitivity and induces vasoconstriction in porcine pulmonary arteries. / Maki, Jun; Hirano, Mayumi; Hoka, Sumio; Kanaide, Hideo; Hirano, Katsuya.

:: British Journal of Pharmacology, 巻 159, 番号 4, 01.02.2010, p. 919-927.

研究成果: ジャーナルへの寄稿記事

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abstract = "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 1AP), but not PAR 4AP. The thrombin-induced contraction was associated with a small elevation of Ca 2+ i and an increase in MLC20 phosphorylation. Thrombin and PAR 1AP 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 -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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AU - Hirano, Mayumi

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AU - Kanaide, Hideo

AU - Hirano, Katsuya

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N2 - 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 1AP), but not PAR 4AP. The thrombin-induced contraction was associated with a small elevation of Ca 2+ i and an increase in MLC20 phosphorylation. Thrombin and PAR 1AP 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 -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.

AB - 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 1AP), but not PAR 4AP. The thrombin-induced contraction was associated with a small elevation of Ca 2+ i and an increase in MLC20 phosphorylation. Thrombin and PAR 1AP 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 -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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