Pathophysiological role of chymase in complications of metabolic syndrome

• Project/Area Number: 20590265
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Osaka Medical College
• Principal Investigator: TAKAI Shinji Osaka Medical College, 医学部, 准教授 (80288703)
• Co-Investigator(Kenkyū-buntansha): JIN Denan 大阪医科大学, 医学部, 講師 (90319533)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: キマーゼ / メタボリックシンドローム / 糖尿病 / 高脂血症 / 臓器障害 / 脂肪肝 / 線維化 / 大動脈瘤 / 高血圧 / 動脈硬化 / 肝線維化 / 阻害薬 / 内皮機能障害 / 臓器線維化

Research Abstract

Chymase converts precursors of angiotensin (Ang) II, Transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9 to their active forms. In a diabetic animal model, chymase induced pancreatic disorganization by augmentation of chymase-forming Ang II. In an animal model with abdominal aneurysmal aorta (AAA), the inhibition of MMP-9 activation by chymase inhibitor resulted in attenuation of the AAA progression. Steatosis and fiblosis in liver were strongly prevented by chymase inhibition in an animal model with nonalcoholic steatohepatitis. These results demonstrated that chymase plays a crucial role in complications of metabolic syndrome.

Research Products

• [Journal Article] Candesartan and amlodipine combination therapy provides powerful vascular protection in stroke-prone spontaneously hypertensive rats (2011)
  • Author(s): Shinji Takai
  • Journal Title: Hypertension Research Volume: 34 Pages: 245-252
  • NAID: 10031163160
  • Peer Reviewed
• [Journal Article] Targets of chymase inhibitors (2011)
  • Author(s): Shinji Takai
  • Journal Title: Expert Opinion on Therapeutic Targets Volume: 15 Pages: 519-527
  • Peer Reviewed
• [Journal Article] Chymase as an important target for preventing complications of metabolic syndrome. (2010)
  • Author(s): Takai S, Jin D, Miyazaki M
  • Journal Title: Curr Med Chem 17 Pages: 3223-3229
  • Peer Reviewed
• [Journal Article] Chymase as an important target for preventing complications of metabolic syndrome (2010)
  • Author(s): Shinji Takai
  • Journal Title: Current Medicinal Chemistry Volume: 17 Pages: 3223-3229
  • Peer Reviewed
• [Journal Article] New approaches to blockade of the renin-angiotensin-aldosterone system : chymase as an important target to prevent organ damage (2010)
  • Author(s): Shinji Takai
  • Journal Title: Journal of Pharmacological Sciences Volume: 113 Pages: 301-309
  • NAID: 10027745795
  • Peer Reviewed
• [Journal Article] Chymase inhibition attenuates tetrachloride-induced liver fibrosis in hamsters (2010)
  • Author(s): Koji Komeda
  • Journal Title: Hepatology Research Volume: 40 Pages: 832-840
  • Peer Reviewed
• [Journal Article] Chymase inhibitor prevents the nonalcoholic steatohepatitis in hamsters fed a methionine- and choline-deficient diet (2010)
  • Author(s): Keitaro Tashiro
  • Journal Title: Hepatology Research Volume: 40 Pages: 514-523
  • Peer Reviewed
• [Journal Article] Captopril directly inhibits matrix metalloproteinase-2 activity in continuous ambulatory peritoneal dialysis therapy (2010)
  • Author(s): Daisuke Yamamoto
  • Journal Title: Clinica Chimica Acta Volume: 411 Pages: 762-764
  • Peer Reviewed
• [Journal Article] Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats (2010)
  • Author(s): Shinji Takai
  • Journal Title: Hypertension Research Volume: 33 Pages: 953-959
  • NAID: 10026711303
  • Peer Reviewed
• [Journal Article] Impact of acute myocardial ischemia reperfusion on the tissue and blood-born renin-angiotensm system (2010)
  • Author(s): Shizu Oyamada
  • Journal Title: Basic Research in Cardiology Volume: 105 Pages: 513-522
  • Peer Reviewed
• [Journal Article] Significance of chymase-dependent matrix metalloproteinase-9 activation on indomethacin-induced small intestinal damages in rats (2010)
  • Author(s): Kazuki Kakimoto
  • Journal Title: J.Pharmacol.Exp.Ther. 332 Pages: 684-689
  • Peer Reviewed
• [Journal Article] Effects of chymase inhibitor on angiotensin II-induced abdominal aortic aneurysm development in apolipoprotein E-deficient mice. (2009)
  • Author(s): Inoue N, Jin D, Takai S, et al
  • Journal Title: Atherosclerosis 204(2) Pages: 359-364
  • Peer Reviewed
• [Journal Article] Chymase-dependent conversion of exogenously administered big endothelin-1 in the mouse in vivo. (2009)
  • Author(s): Simard E, Jin D, Takai S, et al
  • Journal Title: J Pharmacol Exp Ther 328(2) Pages: 540-548
  • Peer Reviewed
• [Journal Article] Long-term angiotensin II blockade may improve not only hyperglycemia but also age-associated cardiac fibrosis. (2009)
  • Author(s): Jin D, Takai S, et al
  • Journal Title: J Pharmacol Sci 109(2) Pages: 275-284
  • NAID: 10025734617
  • Peer Reviewed
• [Journal Article] Chymase plays an important role in left ventricular remodeling induced by intermittent hypoxia in mice. (2009)
  • Author(s): Matsumoto C, Jin D, Takai S, et al
  • Journal Title: Hypertension 54(1) Pages: 164-171
  • Peer Reviewed
• [Journal Article] Chymase inhibition provides pancreatic islet protection in hamsters with streptozotocin-induced diabetes (2009)
  • Author(s): Shinji Takai
  • Journal Title: J.Pharmacol.Sci. 110 Pages: 459-465
  • NAID: 10025738252
  • Peer Reviewed
• [Journal Article] Effects of chymase inhibitor on angiotensin II-induced abdominal aortic aneurysm development in apolipoprotein E-deficient mice (2009)
  • Author(s): Nao Inoue
  • Journal Title: Atherosclerosis 204 Pages: 359-364
  • Peer Reviewed
• [Journal Article] Chymase plays an important role in left ventricular remodeling induced by intermittent hypoxia in mice (2009)
  • Author(s): Chika Matsumoto
  • Journal Title: Hypertension 54 Pages: 164-171
  • Peer Reviewed
• [Journal Article] Anti-atherosclerotic effects of dihomo-γ-linolenic acid in apoE-deficient mice (2009)
  • Author(s): Shinji Takai
  • Journal Title: J.Atheroscler.Thromb. 16 Pages: 480-488
  • NAID: 10025766711
  • Peer Reviewed
• [Journal Article] Involvement of vascular angiotensin II-forming enzymes in the progression of aortic abdominal aneurysms in angiotensin II-infused apoE-deficient mice (2009)
  • Author(s): Nao Inoue
  • Journal Title: J.Atheroscler.Thromb. 16 Pages: 359-364
  • Peer Reviewed
• [Journal Article] Long-term angiotensin II blockade may improve not only hyperglycemi a but also age-associated cardiac fibrosis (2009)
  • Author(s): Jin Denan (金徳男)
  • Journal Title: J. Pharmacol. Sci. 109 Pages: 275-284
  • Peer Reviewed
• [Presentation] Chymase as a useful target to prevent abdominal aortic aneurysm. (2011)
  • Author(s): Takai S, Jin D, Miyazaki M
  • Organizer: Keystone Symposia
  • Place of Presentation: リノ、米国
  • Year and Date: 2011-01-26
• [Presentation] Chymase as a useful target to prevent abdominal aortic aneurysm (2011)
  • Author(s): Shinji Takai
  • Organizer: Keystone Symposia
  • Place of Presentation: Granlibakken Ressort (California, USA)
  • Year and Date: 2011-01-26
• [Presentation] キマーゼ阻害薬による腹部大動脈瘤予防の可能性 (2010)
  • Author(s): 高井真司
  • Organizer: 第38回薬物活性シンポジウム
  • Place of Presentation: 札幌市教育文化会館(北海道)
  • Year and Date: 2010-11-12
• [Presentation] キマーゼ阻害薬による腹部大動脈瘤進展予防の可能性(シンポジウム) (2010)
  • Author(s): 高井真司、金徳男、宮崎瑞夫
  • Organizer: 第38回薬物活性シンポジウム
  • Place of Presentation: 札幌
  • Year and Date: 2010-11-11
• [Presentation] カンデサルタンとアムロジピンの併用投与による血管保護相乗効果の機序 (2010)
  • Author(s): 高井真司
  • Organizer: 日本高血圧学会
  • Place of Presentation: 福岡国際会議場(福岡)
  • Year and Date: 2010-10-15
• [Presentation] Combination therapy with angiotensin receptor blocker and T- and L-type calcium channel blocker for attenuation of proteinuria in Dahlsalt-sensitive rats (2010)
  • Author(s): Shinji Takai
  • Organizer: 23rd Scientific Meeting of the International Society of Hypertension
  • Place of Presentation: Vancouver Convention Centre (Vancouver, Canada)
  • Year and Date: 2010-09-27
• [Presentation] Combination therapy with angiotensin receptor blocker and T- and L-type calcium channel blocker for attenuation of proteinuria in Dahl-salt sentitive rats. (2010)
  • Author(s): 高井真司, 金徳男, et al
  • Organizer: 23rd Scientific Meeting of the International Society of Hypertension
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2010-09-26
• [Presentation] キマーゼ阻害薬による腹部大動脈瘤の進展抑制 (2010)
  • Author(s): 高井真司
  • Organizer: 生体機能と創薬シンポジウム2010京都
  • Place of Presentation: ホテルグランビア京都(京都)(招待講演)
  • Year and Date: 2010-09-09
• [Presentation] キマーゼ阻害薬のターゲット疾患について(シンポジウム) (2010)
  • Author(s): 高井真司、金徳男、宮崎瑞夫
  • Organizer: 第15回日本病態プロテアーゼ学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2010-08-20
• [Presentation] キマーゼ阻害薬のターゲット疾患について (2010)
  • Author(s): 高井真司
  • Organizer: 第15回日本病態プロテアーゼ学会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪)(招待講演)
  • Year and Date: 2010-08-20
• [Presentation] 特異的キマーゼ阻害薬TY-51469によるハムスター非アルコール性脂肪性肝炎の阻害効果 (2010)
  • Author(s): 山本裕美
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2010-03-16
• [Presentation] 非アルコール性脂肪性肝炎(NASH)ハムスターモデルにおけるキマーゼ阻害薬の効果 (2009)
  • Author(s): 田代圭太郎
  • Organizer: 第14回日本病態プロテアーゼ学会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪)
  • Year and Date: 2009-08-21
• [Presentation] キマーゼ阻害薬の開発と臓器保護効果(シンポジウム) (2009)
  • Author(s): 高井真司、金徳男、宮崎瑞夫
  • Organizer: 日本薬理学会
  • Place of Presentation: 横浜
  • Year and Date: 2009-03-16
• [Presentation] キマーゼ阻害薬の開発と臓器保護効果 (2009)
  • Author(s): 高井真司
  • Organizer: 第82回日本薬理学会年会(シンポジウム)
  • Place of Presentation: 横浜
  • Year and Date: 2009-03-16
• [Book] 日本臨床 高血圧(第4版) 上巻 (2009)
  • Author(s): 高井真司
  • Publisher: 日本臨床社
• [Remarks] ホームページ等