The Role for Cysteine Protease Cathepsin in Left Ventricular Remodeling and Gene Therapy Application.

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17590719
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Nagoya University
• Principal Investigator: CHENG Xianwu Nagoya University, School of Medicine, Research Associate, 医学部, 助手 (30378228)
• Co-Investigator(Kenkyū-buntansha): KAZUYA Masafumi Nagoya University, Graduate School of Medicine, Associate Professor, 大学院医学系研究科, 助教授 (10283441) ; NAGATA Kouzou Nagoya University, School of Medicine, Associate Professor, 医学部, 助教授 (20378227) ; KONDO Takahisa University Hospital, Assistant Professor, 医学部附属病院, 講師 (00303644) ; IGUCHI Aakihisa Nagoya University, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (20109763)
• Project Period (FY): 2005 – 2006
• Keywords: Ventricular Remodeling / Protease-Cathepsin S / Hypertension / Heart Failure / Cardiomyocyte / Olmesartan

Research Abstract

Background : Cathepsin activation contributes to tissue remodeling in several disease states. The present study tested the hypothesis that cathepsin inhibition prevents LV remodeling and dysfunction in the development of CHF associated with hypertension.
Methods and Results : Dahl salt-sensitive rats fed an 8% NaCl diet from age 7 weeks served as a CHF model arbitrarily assigned to three treatment groups at age 12 weeks. The abundance of cathepsin mRNAs and proteins localized in cardiac myocytes (CMCs) and cathepsin-dependent activities were increased in the left ventricle of CHF rats, and were reduced by olmesartan treatment. Olmesartan suppressed the elastic lamina degradation concomitant with decreased local cathepsin S expression in intracoronary smooth muscle cells (SMCs) and restored the ratio of elastin to collagen in CHF rats. Furthermore, olmesartan suppressed not only interleukin-1β expression and macrophage infiltration but also levels of NADPH oxidase components (p22^<phox>, gp91^<phox>, and p47^<phox>) concomitant with decreased NADPH activity and O_2^- production in CHF rats. These were accompanied by improved cardiac fibrosis, stiffness, and dysfunction. Interestingly, all of these improvements were observed by E64d. The antioxidants MnTmPyp and N-acetylcysteine inhibited the H2O2-induced increase in cathepsin expression and elastolytic activity in culture CMCs and SMC.
Conclusions : These results suggest that cathepsins are likely to trigger and promote LV remodeling, and that olmesartan-mediated inhibition of angiotensin type1 receptor inhibits cathepsins by suppressing inflammation and oxidative stress, leading to the prevention of cardiac remodeling and dysfunction.

Research Products

• [Journal Article] Mechanisms underlying the impairment of ischemia-induced neovascularization in MMP-2-deficient mice. (2007)
  • Author(s): Cheng XW, Kuzuya M, Nakamura K, Maeda K, Tsuzuki M, Kim W, Sasaki T, Liu Z, Kondo T, Jin H, Numaguchi Y, Okumura K, Yokota T, Iguchi A, Murohara T
  • Journal Title: Circulation Research. 100 Pages: 904-913
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Impact of High-Molecular Weight Form of Adiponectin on Endothelial Function in Healthy Young Men. (2007)
  • Author(s): Torigoe M, Matsui H, Ogawa Y, Murakami H, Murakami R, Cheng XW, Numaguchi Y, Murohara T, Okumura K
  • Journal Title: Clinical Endocrinology. (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mechanisms underlying the impairment of ischemia-Induced neovascularization in MMP-2-deficient mice. (2007)
  • Author(s): Cheng XW, Kuzuya M, Nakamura K, Maeda K, Tsuzuki M, Kim W, Sasaki T, Li Z, Kondo T, Jin H, Numaguchi Y, Okumura K, Yokota T, Iguchi A, Murohara T
  • Journal Title: Circulation Research. 100 Pages: 904-913
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Impact of High-Molecular Weight Form of Adiponectin on Endothelial Function in Healthy Young Men. (2007)
  • Author(s): Torigoe M, Matsui H, Ogawa Y, Murakami H, Murakami R, Cheng XW, Numaguchi Y, Murohara T, Okumura K
  • Journal Title: Clinical Endocrinology. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Localization of Cysteine Protease, Cathepsin S, to the Surface of Vascular smooth muscle cells by association with integrin αυβ3 (2006)
  • Author(s): Cheng XW, kuzuya M, Nakamura K, Di Q, Liu Z, Sasaki T, Iguchi A
  • Journal Title: American Journal of Pathology 168 Pages: 685-694
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Underuse of Medications for Chronic Diseases in the Oldest of Community-Dwelling Older Frail Japanese. (2006)
  • Author(s): Kuzuya M, Masuda Y, Hirakawa Y, Iwata M, Enoki H, Hasegawa Y, Cheng XW, Iguchi A
  • Journal Title: Journal of American Geriatrics 54 Pages: 598-605
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of MMP-2 deficiency on atherosclerotic lesion formation in ApoE-deficient Mice (2006)
  • Author(s): Kuzuya M, Nakamura, Sasaki T, Cheng XW, Shigeyoshi I, Iguchi A
  • Journal Title: Arterioscleosisr Thrombosis and Vascular Biology. 26 Pages: 1120-1125
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A simple method of Plaque Rupture Formation in Apo-E Deficient mice. (2006)
  • Author(s): Sasaki T, Kuzuya M, Nakamura K, Cheng XW, Sato K, Iguchi A
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology 26 Pages: 1304-1309
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure. (2006)
  • Author(s): Saka M, Obata K, Ichihara S, Cheng XW, Kimata H, Takao Nishizawa, Noda K, Izawa H, Nagata K, Murohara T, Yokota M
  • Journal Title: Journal of Cardiovascular Pharmacology 47 Pages: 770-779
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of Green Tea Consumption on Endothelial Function and Circulating Endothelial Progenitor Cells in Chronic Smokers. (2006)
  • Author(s): Kim W, Jeong MH, Cho SH, Yun HY, Chae HJ, Ahn YK, Lee MC, Cheng XW, Kondo T, Murohara T, Kang JC
  • Journal Title: Circulation Journal 70 Pages: 1052-1057
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A Elastolytic Cathepsin Induction/Activation System Exists in the Rat and Human Myocardium and is Upregulated in Hypertensive Heart Failure. (2006)
  • Author(s): Cheng XW, Obata K, Kzuya M, Izawa H, Nakamura K, Asahi E, Saka M, Kimata T, Nagasaka T, Noda A, Nagata K, Jin H, Shi GP, Iguchi A, Murohara T, Yokota M
  • Journal Title: Hypertension 48 Pages: 979-987
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Attenuation of ventricular hypertrophy and fibrosis in rats by pitavastatin : potential role of the RhoA-ERK-SRF signaling pathway. (2006)
  • Author(s): Saka M, Obata K, Ichihara S, Cheng XW, Kimata H, Noda K, Nagata K, Yokota M
  • Journal Title: Clinical and Experimental Pharmacology and Physiology 33 Pages: 1164-1171
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Localization of Cysteine Protease, Cathepsin S, to the Surface of Vascular smooth muscle cells by association with integrin ανβ3. (2006)
  • Author(s): Cheng XW, Kuzuya M, Nakamura K, Di Qun, Liu Z, Sasaki T, Murohara T, Yokota M, Iguchi A
  • Journal Title: American Journal of Pathology 168 Pages: 685-694
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effect of MMP-2 deficiency on atherosclerotic lesion formation in ApoE-deficient Mice. (2006)
  • Author(s): Kuzuya M, Nakamura K, Sasaki T, Cheng XW, Itohara S, Iguchi A
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology 26 Pages: 1120-1125
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A simple method of Plaque Rupture Formation in Apo-E Deficient mice. (2006)
  • Author(s): Sasaki T, Kuzuya M, Nakamura K, Cheng XW, Sato K, Iguchi A.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology 26 Pages: 1304-1309
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure. (2006)
  • Author(s): Saka M, Obata K, Ichihara S, Cheng XW, Kimata H, Takao N, Noda K, Izawa H, Nagata K, Murohara T, Yokota M.
  • Journal Title: Journal of Cardiovascular Pharmacology 47 Pages: 770-779
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A Elastolytic Cathepsin Induction/Activation System Exists in the Rat and Human Myocardium and is Upregulated in Hypertensive Heart Failure. (2006)
  • Author(s): Cheng XW, Obata K, Kzuya M, Izawa H, Nakamura K, Asahi E, Saka M, Kimata T, Nagasaka T, Noda A, Nagata K, Jin H, Shi G P, Iguchi A, Murohara T, Yokota M
  • Journal Title: Hypertension 48 Pages: 979-987
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mechanisms of the Inhibitory Effect of Epigallocatechin-3-gallate on Cultured Human Vascular Smooth Muscle Cell Invasion (2005)
  • Author(s): Cheng XW, kuzuya M, Nakamura K, Liu Z, Di Q, Sasaki T, Iguchi A
  • Journal Title: Arterioscleosisr Thrombosis and Vascular Biology. 25 Pages: 1864-1870
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mechanisms of the Inhibitory Effect of Epigallocatechin-3-gallate on Cultured Human Vascular Smooth Muscle Cell Invasion (2005)
  • Author(s): Cheng XW, Kuzuya M, Nakamura K, Di Qun, Liu Z, Hasegawa J, Iwata M, Murohara T, Yokota M, Iguchi A
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology 25 Pages: 1864-1870
  • Description: 「研究成果報告書概要(欧文)」より