2003 Fiscal Year Annual Research Report

血管攣縮の分子機構:平滑筋Ca感受性亢進に関与する細胞内情報伝達網の解明

Research Project

Project/Area Number	13470149
Research Institution	KYUSHU UNIVERSITY
Principal Investigator	金出英夫九州大学, 大学院・医学研究院, 教授 (80038851)
Co-Investigator(Kenkyū-buntansha)	平野勝也九州大学, 大学院・医学研究院, 講師 (80291516) 西村淳二九州大学, 大学院・医学研究院, 助教授 (90237727)
Keywords	Protease-actvated receptors / トロンビン受容体 / 血管平滑筋細胞 / クモ膜下出血 / 細胞質[Ca^<++>]i / トロンビン / 血管攣縮
Research Abstract	炎症、出血、動脈硬化病変部ではprotease-actvated receptors (PARs)の発現亢進が知られている。PARsの1つにトロンビン受容体がある。トロンビンはフィブリノーゲンをフィブリンに転換する事によって血液凝固に関与する。一方、ヒトのクモ膜下出血ではしばしば脳動脈攣縮が起き、命取りとなることがよく知られている。クモ膜下出血の予備実験で次の結果を得た。正常家兎脳底動脈の摘出血管平滑筋標本はトロンビン添加によって、本来、わずかに緊張するのみである。ところが、クモ膜下に自家血を少量注入し、クモ膜下出血と同様の状態に曝すと、脳底動脈のトロンビン誘発性緊張は目毎に増大し、7-10日目に頂点に達する。すなわち、極微量のトロンビン添加でも、正常標本の30倍強度の持続的張力発生、いわゆる、強烈な血管攣縮が観察された。張力発生は局所平滑筋[Ca^<++>]iの著しい上昇を伴った。自家血をヘパリン化して注入した場合には、この現象は見られない。したがって、自家血の凝固によって生じた少量のトロンビンが血管に作用し、作用7-10日目を頂点にトロンビン自身に対する著しい緊張亢進状態を作り出していることになる。平滑筋のトロンビン受容体mRNAは、この緊張反応の増大に見合う量の増加を示した。この、「出血-トロンビン少量産生-平滑筋トロンビン受容体の過剰発現-トロンビン誘発の血管攣縮発現」という機序は、全く新しい攣縮の機序であり、重要な発見である。冠動脈攣縮モデル豚の強烈な攣縮局所血管にも微量の出血が見られることから、冠動脈攣縮においても、トロンビンの関与が強く示唆される。

Research Products

(12 results)

All Other

All Publications (12 results)

[Publications] Nakayama T: "Unproductive cleavage and inactivation of protease-activated receptor-1 by trypsin in vascular endotheial cells."Br J Pharmacol. 138. 121-130 (2003)
[Publications] Fukuyama K: "Down regulation of vascular angiotensin II type 1 receptor by thyroid hormone."Hypertension. 41. 598-603 (2003)
[Publications] Takahashi R: "The modulation of Ca^<2+> sensitivity regulates contractility of rabbit corpus cavernosum smooth muscle."J Urology. 169. 2412-2416 (2003)
[Publications] Hirano K: "Sequence requirement for nuclear localization and growth inhibition of p27^<Kip1R>, a degradation-resistant isoform of p27^<Kip1>."J Cell Biochem. 89. 191-202 (2003)
[Publications] Yamanaka J: "An important role for the Na^+-Ca^<2+> exchanger in the decrease in cytosolic Ca^<2+> concentration induced by isoprenaline in the porcine coronary artery."J Physiol. 549. 553-562 (2003)
[Publications] Eto W: "Intracellular alkalinization induces Ca^<2+> influx via non-voltage-operated Ca^<2+> channels in the rat aortic smooth muscle cells."Cell Calcium 34 : 477-484,2003. 34. 477-484 (2003)
[Publications] Maeda Y: "Rho-kinase inhibitor inhibits both myosin phosphorylation-dependent and -independent enhancement of myofilament Ca^<2+> sensitivity in bovine middle cerebral artery."Br J Pharmacol. 140. 871-880 (2003)
[Publications] Ise S: "Theophylline attenuates Ca^<2+> sensitivity and modulates BK channels in porcine tracheal smooth muscle"Br J Pharmacol. 140. 939-947 (2003)
[Publications] Kanaide H: "Cellular mechanism of vasoconstriction induced by angiotensin II : It remains to be determined."Cir Res. 93. 1015-1017 (2003)
[Publications] Hirano K: "Transduction of the N-terminal fragments of MYPT1 enhances myofilament Ca^<2+> sensitivity in an intact coronary artery."Athersclerosis Thromb Vase Biol. (in press).
[Publications] Nakayama T: "Inactivation of protease activated receptor-1 due to a proteolytic removal of the tethered ilgand by thrombin and trypsin in the human umbilical vein endothelial cells."Biochem Pharmacol. (in press).
[Publications] Koga M: "The long-term deficiency of estrogen enhances the contractile response without affecting the Ca^<2+> sensitivity of the contractile apparatus in arterial smooth muscle of the female rabbit."J Soc Gynecol Invest. (in press).

2003 Fiscal Year Annual Research Report

血管攣縮の分子機構:平滑筋Ca感受性亢進に関与する細胞内情報伝達網の解明

Principal Investigator

金出 英夫 九州大学, 大学院・医学研究院, 教授 (80038851)

Research Products

[Publications] Nakayama T: "Unproductive cleavage and inactivation of protease-activated receptor-1 by trypsin in vascular endotheial cells."Br J Pharmacol. 138. 121-130 (2003)

[Publications] Fukuyama K: "Down regulation of vascular angiotensin II type 1 receptor by thyroid hormone."Hypertension. 41. 598-603 (2003)

[Publications] Takahashi R: "The modulation of Ca^<2+> sensitivity regulates contractility of rabbit corpus cavernosum smooth muscle."J Urology. 169. 2412-2416 (2003)

[Publications] Hirano K: "Sequence requirement for nuclear localization and growth inhibition of p27^<Kip1R>, a degradation-resistant isoform of p27^<Kip1>."J Cell Biochem. 89. 191-202 (2003)

[Publications] Yamanaka J: "An important role for the Na^+-Ca^<2+> exchanger in the decrease in cytosolic Ca^<2+> concentration induced by isoprenaline in the porcine coronary artery."J Physiol. 549. 553-562 (2003)

[Publications] Eto W: "Intracellular alkalinization induces Ca^<2+> influx via non-voltage-operated Ca^<2+> channels in the rat aortic smooth muscle cells."Cell Calcium 34 : 477-484,2003. 34. 477-484 (2003)

[Publications] Maeda Y: "Rho-kinase inhibitor inhibits both myosin phosphorylation-dependent and -independent enhancement of myofilament Ca^<2+> sensitivity in bovine middle cerebral artery."Br J Pharmacol. 140. 871-880 (2003)

[Publications] Ise S: "Theophylline attenuates Ca^<2+> sensitivity and modulates BK channels in porcine tracheal smooth muscle"Br J Pharmacol. 140. 939-947 (2003)

[Publications] Kanaide H: "Cellular mechanism of vasoconstriction induced by angiotensin II : It remains to be determined."Cir Res. 93. 1015-1017 (2003)

[Publications] Hirano K: "Transduction of the N-terminal fragments of MYPT1 enhances myofilament Ca^<2+> sensitivity in an intact coronary artery."Athersclerosis Thromb Vase Biol. (in press).

[Publications] Nakayama T: "Inactivation of protease activated receptor-1 due to a proteolytic removal of the tethered ilgand by thrombin and trypsin in the human umbilical vein endothelial cells."Biochem Pharmacol. (in press).

[Publications] Koga M: "The long-term deficiency of estrogen enhances the contractile response without affecting the Ca^<2+> sensitivity of the contractile apparatus in arterial smooth muscle of the female rabbit."J Soc Gynecol Invest. (in press).

金出英夫九州大学, 大学院・医学研究院, 教授 (80038851)