Cysteine Protease Cathepsin K: A New Biomarker in Patients with Atrial Fibrillation

• Project/Area Number: 24659385
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: Nagoya University
• Principal Investigator: XIAN WU Cheng 名古屋大学, 医学(系)研究科(研究院), 特任准教授 (30378228)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: カテプシンK / 心房細動 / 心房リモデリング / マトリックス蛋白 / バイオマーカー

Research Abstract

We sought to determine the link between atrial fibrillation (AF) and plasma CatK levels and to investigate the expression and therapeutic target for CatK. Plasma levels of CatK were measured in patients with AF (paroxysmal AF [PAF]; persistent AF [PeAF]) and control subjects. AF had higher CatK than did controls. PeAF had higher CatK levels than PAF. CatK was correlated left atrial diameter in all subjects. The levels of atrial tissue angiotensin II, AT1R, gp91phox, p-p38MAPK, and CatK; O2-; and CatK activity; and fibrosis were greater in rabbits with AF than in that of controls, and these changes were reversed by AT1R blocker (ARB). Olmesartan decreased the CatK expression induced by angiotensin II in neonatal myocytes. These data indicated that increased plasma CatK levels are linked with the presence of AF. ARB appears to be effective in alleviating atrial fibrosis in a rabbit AF model, partly reducing AT1R-p38MAPK-dependent and -independent CatK activation, thus preventing AF.

Research Products

• [Journal Article] Cathepsin K-Mediated Notch1 Activation Contributes to Neovascularisation in Response to Hypoxia (2014)
  • Author(s): Jiang H, Cheng XW, Shi GP, Hu L, Inoue A, Yamamura Y, Wu H, Takeshita K, Li X, Huang Z, Song H, Asai M, Hao CN, Unno K, Koike T, Oshida Y, Okumura K, Murohara T, Kuzuya M.
  • Journal Title: Nature Communications Volume: (in press)
  • Peer Reviewed
• [Journal Article] Impact of Lysophosphatidylcholine on Survival and Function of UEA-1^+acLDL^+ Endothelial Progenitor Cells in Patients with Coronary Artery Disease (2014)
  • Author(s): Hong SH, Jang HH, Lee SR, Lee KH, Woo JS, Kim JB, Kim WS, Min BI, Cho KH, Kim KS, Cheng XW, Kim W.
  • Journal Title: Heart & Vessels Volume: (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] β-Hydroxy-β- methylbutyrate facilitates PI3K/Aktdependent mammalian target of rapamycin and FoxO1/3a phosphorylations and alleviates tumor necrosis factor α/ interferon γ-induced MuRF-1 expression in C2C12 cells (2014)
  • Author(s): Kimura K, Cheng XW, Inoue A, Hu L, Koike T, Kuzuya M
  • Journal Title: Nutr Res Volume: 34(4) Issue: 4 Pages: 368-74
  • DOI: 10.1016/j.nutres.2014.02.003
  • Peer Reviewed / Open Access
• [Journal Article] Cathepsin K activity controls injury-related vascular repair in mice. (2014)
  • Author(s): Hu L, Cheng XW, Song H, Inoue A, Jiang H, Li X, Shi GP, Kozawa E, Okumura K, Kuzuya M.
  • Journal Title: Hypertension. Volume: 63(3) Issue: 3 Pages: 607-615
  • DOI: 10.1161/hypertensionaha.113.02141
  • Peer Reviewed
• [Journal Article] Digesting the Atherosclerosis-like Lesion-Based Remodeled Vasculature: The Role of Cysteinyl Cathepsins in Venous Disorder. (2014)
  • Author(s): Cheng XW, Sasaki T, Kuzuya M
  • Journal Title: Thrombosis and Haemostasis Volume: in press Issue: 07 Pages: 216-218
  • DOI: 10.1160/th13-10-0889
  • Peer Reviewed / Open Access
• [Journal Article] β-Hydroxy-β-methylbutyrate facilitates PI3K/Akt-dependent mTOR and FoxO1/3a phosphorylations and alleviates TNF-α/IFN-γ-induced MuRF-1 expression in C2C12 cells. (2014)
  • Author(s): Kimura K, Cheng XW, Inoue A, Hu L, Koike T, Kuzuya M.
  • Journal Title: Nutr Res. Volume: -
  • Peer Reviewed
• [Journal Article] The role of cysteinyl cathepsins in venous disorders. (2014)
  • Author(s): Cheng XW, Sasaki T, Kuzuya M.
  • Journal Title: Thrombosis and Heamostasis. Volume: -
  • Peer Reviewed
• [Journal Article] Cathepsin K-Mediated Notch1 Activation Contributes to Neovascularisation in Response to Hypoxia. (2014)
  • Author(s): Jiang H, Cheng XW, Shi GP, Hu L, Inoue A, Yamamura Y, Wu H, Takeshita K, Li X, Huang Z, Song H, Asai M, Hao CN, Unno K, Koike T, Oshida Y, Okumura K, Murohara T, Kuzuya M.
  • Journal Title: Nature Communications. Volume: -
  • Peer Reviewed
• [Journal Article] Circulating cathepsin K as a potential novel biomarker of coronary artery disease. (2013)
  • Author(s): Cheng XW, Kikuchi R, Ishii H, Yoshikawa D, Hu L, Takahashi R, Shibata R, Ikeda N, Kuzuya M, Okumura K, Murohara T.
  • Journal Title: Atherosclerosis. Volume: 228(1) Issue: 1 Pages: 211-216
  • DOI: 10.1016/j.atherosclerosis.2013.01.004
  • Peer Reviewed
• [Journal Article] Injury in STEMI Patients Undergoing PCI: Something New and Promising, or Not? (2013)
  • Author(s): Cheng XW, Murohara T, Kuzuya M.
  • Journal Title: IJC Metabolic & Endocrine Volume: １ Pages: 1-3
  • DOI: 10.1016/j.ijcme.2013.10.003
  • Peer Reviewed
• [Journal Article] Relationship of myocardial fibrosis to left ventricular and mitochondrial function in nonischemic dilated cardiomyopathy--a comparison of focal and interstitial fibrosis (2013)
  • Author(s): Yamada T, Hirashiki A, Cheng XW, Okumura T, Shimazu S, Okamoto R, Shinoda N, Isobe S, Takeshita K, Naganawa S, Kondo T, Murohara T
  • Journal Title: J Card Fail Volume: 8 Issue: 8 Pages: 557-64
  • DOI: 10.1016/j.cardfail.2013.05.018
  • Peer Reviewed
• [Journal Article] Regulation of Apelin and its Receptor Expression in Adipose Tissues of Obesity Rats with Hypertension and Cultured 3T3-L1 Adipocytes (2013)
  • Author(s): Wu HX, Cheng XW, Hao C, Zhang Z, Yao H, Murohara T, Dai Q.
  • Journal Title: Experimental Animals Volume: (acceptance)
  • NAID: 130003391623
  • Peer Reviewed
• [Journal Article] Circulating cf-DNA : A Promising, Noninvasive Tool for Assessment of Early Cardio-Metabolic Risk (editorials) (2013)
  • Author(s): Song H, Nan YS, Cheng XW.
  • Journal Title: Atherosclerosis Volume: 233 Issue: 1 Pages: 307-309
  • DOI: 10.1016/j.atherosclerosis.2013.11.081
  • Peer Reviewed
• [Journal Article] Association between cardiopulmonary mparison with peak VO₂and VE/VCO₂slope (2013)
  • Author(s): Okumura T, Hirashiki T, Yamada S, Funahashi H, Oshima S, Kono Y, Cheng XW, Takeshita K, Muroahra T.
  • Journal Title: International Journal of Cardiology Volume: 162(3) Issue: 3 Pages: 234-239
  • DOI: 10.1016/j.ijcard.2011.05.065
  • Peer Reviewed
• [Journal Article] Usefulness of Serum Cardiac Troponins T and I to Predict Cardiac Molecular Changes and Cardiac Damage in Patients With Hypertrophic Cardiomyopathy (2013)
  • Author(s): Okamoto R, Hirashiki A, Cheng XW, Shinoda N, Okumura T, Takeshita K, Bando Y, Murohara T.
  • Journal Title: International Heart Journal Volume: 54 Issue: 4 Pages: 202-206
  • DOI: 10.1536/ihj.54.202
  • NAID: 130003364470
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed
• [Journal Article] Increased 99m Tc-sestamibi Washout Reflects Impaired Myocardial Contractile and Relaxation Reserve during Dobutamine Stress Due to Mitochondrial Dysfunction in Dilated Cardiomyopathy Patients. (2013)
  • Author(s): Hayashi D, Ohshima S, Isobe S, Cheng XW, Unno K, Funahashi H, Shinoda N, Okumura T, Hirashiki A, Kato K, Murohara T.
  • Journal Title: J Am Coll Cardiol Volume: 1 Issue: 19 Pages: 1-2
  • DOI: 10.1016/j.jacc.2013.01.074
  • Peer Reviewed
• [Journal Article] Effects of Aged Garlic Extract on Left Ventricular Diastolic Function and Fibrosis in a Rat Hypertension Model (2013)
  • Author(s): Hara Y, Noda A, Miyata S, Minoshima M, Sugiura M Kojima J, Otake M, Furukawa M, Cheng XW, Nagota K, Murohara T.
  • Journal Title: Experimental Animals Volume: 62 Issue: 4 Pages: 305-310
  • DOI: 10.1538/expanim.62.305
  • NAID: 130003382711
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed
• [Journal Article] The power combination of blood-pressure parameers to predict the incidence of plaque formation in carotid arteries in elderly (2013)
  • Author(s): Hao CH, Shi YQ, Huang JJ, Li HY, Huang ZH, Cheng XW, Lu W, Duan JL.
  • Journal Title: International Journal of Clinical and Experimental Medicine Volume: 6(6) Pages: 461-469
  • URL: http://www.ijcem.com/ISSN:1940-5901/IJCEM1305006
  • Peer Reviewed
• [Journal Article] Mechanisms with clinical implications for atrial fibrillation-associated remodeling: cathepsin K expression, regulation, and therapeutic target and biomarker. (2013)
  • Author(s): Fujita M, Cheng XW, Inden Y, Shimano M, Yoshida N, Inoue A, Yamamoto T, Takeshita K, Kyo S, Taguchi N, Shi GP, Kuzuya M, Okumura K, Murohara T.
  • Journal Title: J Am Heart Assoc. Volume: 2 Issue: 6
  • DOI: 10.1161/jaha.113.000503
  • Peer Reviewed
• [Journal Article] Matrix Metalloproteinase-2 deficiency Impairs Aortic Atherosclerotic Calcification in atherosclerotic in ApoE- deficient old mice (2013)
  • Author(s): Sasaki T, Nakamura K, Sasada K, Okata S, Cheng XW, Suzuki S, Murohara T, Sato K, Kuzuya M.
  • Journal Title: Atherosclerosis Volume: 227 Pages: 43-50
  • Peer Reviewed
• [Journal Article] Matrix metalloproteinase-2 deficiency impairs aortic atherosclerotic calcification in ApoE-deficient mice. (2013)
  • Author(s): Sasaki T, Nakamura K, Sasada K, Okada S, Cheng XW, Suzuki T, Murohara T, Sato K, Kuzuya M.
  • Journal Title: Atherosclerosis. Volume: 227(1) Issue: 1 Pages: 43-50
  • DOI: 10.1016/j.atherosclerosis.2012.12.008
  • Peer Reviewed
• [Journal Article] Impacts of Combination of Angiotensin II Receptor Blocker and Low-dose Hydrochlothiazide on Patietns with Morning Hypertension. (2012)
  • Author(s): Cheng XW.
  • Journal Title: Hypertension Research (Commentary) Volume: 35(7) Pages: 702-703
  • Peer Reviewed
• [Journal Article] Blood Pressure Variability and Vascular Dysfunction in Essential Hypertension (Review). (2012)
  • Author(s): Okumura K.
  • Journal Title: Journal of Korean Society of Hypertension Volume: 18(3) Pages: 75-87
  • Peer Reviewed
• [Journal Article] Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and -independent actions (2012)
  • Author(s): Shigeta T, Aoyama M, Bando YK, Monji A, Mitsui T, Takatsu M, et al.
  • Journal Title: Circulation Volume: 126 Issue: 15 Pages: 1838-1851
  • DOI: 10.1161/circulationaha.112.096479
  • Peer Reviewed
• [Journal Article] Predictive value of heart rate recovery after exercise testing in addition to brain natriuretic Peptide levels in ambulatory patients with nonischemic dilated cardiomyopathy (2012)
  • Author(s): Shinoda N, Hirashiki A, Okumura T, Okamoto R, Wu Cheng X, Kono Y, Takeshita K, Yamada S, Murohara T
  • Journal Title: Ann Noninvasive Electrocardiol Volume: 17(4) Issue: 4 Pages: 378-86
  • DOI: 10.1111/j.1542-474x.2012.00542.x
  • Peer Reviewed
• [Journal Article] Small Low-Density Lipoprotein Cholesterol Concentration is a Determinant of Endothelial Dysfunction by Peripheral Artery Tonometry in Men. (2012)
  • Author(s): Okumura K.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 19 Pages: 897-903
  • Peer Reviewed
• [Presentation] The Progress in Angiogenesis Research : Focusing on Notch1 Activation and Cathepsin K (2013)
  • Author(s): Cheng XW.
  • Organizer: Myocardial Ischemia Symposium in Korea 2013 (MIS-Korea)
  • Place of Presentation: ソウル(韓国)
  • Year and Date: 2013-09-28
• [Presentation] Cathepsin K-A Classical Bone Biomarker in Cardiovascular Disease : The heart is not alone anymore (2013)
  • Author(s): Cheng XW.
  • Organizer: The 3rd East Asia International Cardiovascular Symposium
  • Place of Presentation: 哈爾濱(中国)
  • Year and Date: 2013-08-09
• [Presentation] Mechanisms Underlying the Impairment of Ischemia- Induced Neovascularization in Cathepsin K- Deficient Mice : Impact on Noich1 activation (2013)
  • Author(s): 姜海英,成憲武,胡麗娜,井上愛子,史国平,奥村健二,葛谷雅文
  • Organizer: 第77回日本循環器学会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2013-03-15
• [Presentation] Statin Prevented Apoptosis of Vascular Smooth Muscle Cells and Atherosclerotic Plaque Disruption in ApoE-/- mouse model. (2013)
  • Author(s): 成憲武.
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
• [Presentation] Mechanisms Underlying the Impairment of Ischemia-Induced Neovascularization in Cathepsin K-Deficient Mice: Impact on Noich1 activation. (2013)
  • Author(s): Haiying Jiang.
  • Organizer: 第77回日本循環器学会
  • Place of Presentation: パシフィコ横浜(神奈川県)
• [Presentation] Cathepsin K as A New Therapeutic Target and Biomarker for Cardiovascular Disease. (2013)
  • Author(s): Cheng XW.
  • Organizer: 3rd Kyung Hee University Atherosclerosis Symposium: Cardiac Biomarker from bench to beside
  • Place of Presentation: Seoul, Korea
  • Invited
• [Presentation] The Progress in Angiogenesis Research: Focusing on Notch1 Activation and Cathepsin K. (2013)
  • Author(s): Cheng XW.
  • Organizer: Myocardial Ischemia Symposium in Korea 2013 (MIS-Korea).
  • Place of Presentation: Seoul, Korea
  • Invited
• [Presentation] Mechanisms Underlying the Impairment of Ischemia-Induced Neovascularization in Cathepsin K-Deficient Mice (2012)
  • Author(s): Jiang HY, Cheng XW, Shi GP, Hu L, Inoue A, Song H, Huang Z, Okumura K, Kuzuya M.
  • Organizer: American Heart Association.Scientific Sections 2012
  • Place of Presentation: ロサンゼルス(アメリカ)
  • Year and Date: 2012-11-05
• [Presentation] Anti-Vascular Aging : Impact on Exercise and EPCs (2012)
  • Author(s): Cheng XW.
  • Organizer: The 3rd International Symposium on the Frontiers in Cardiovascular Diseases (3rd ISFC)
  • Place of Presentation: 廈門市(中国)
  • Year and Date: 2012-09-22
• [Presentation] Cysteine Protease Cathepsin K : A New Biomarker in Patients with Atrial Fibrillation (2012)
  • Author(s): 藤田雅也,成憲武,因田恭也,吉田直樹,嶋野祐之,奥村健二,室原豊明
  • Organizer: 第60回日本心臓病学会学術集会
  • Place of Presentation: ホテル日航金沢ほか(金沢市)
  • Year and Date: 2012-09-15
• [Presentation] Exploration of Mechanisms of Atherosclerotic Plaque Rupture From A New and Simple Mouse Model of Plaque Rupture (2012)
  • Author(s): 成憲武,胡麗娜,井上愛子,佐々木健,木村薫,室原豊明,葛谷雅文
  • Organizer: 第44回日本動脈硬化学会総会・学術集会(シンポジウム)
  • Place of Presentation: ヒルトン福岡シーホーク(福岡市)
  • Year and Date: 2012-07-19
• [Presentation] Stains Enhance the Beneficial Effects of Olmesartan on Renal Injury in Salt-induced Hypertension in Dalh Rat Model. (2012)
  • Author(s): 成憲武.
  • Organizer: 第44回日本動脈硬化学会
  • Place of Presentation: ヒルトン 福岡シーホーク(福岡県)
• [Presentation] Mechanism Underlying the Impairment of Ischemia-Induced Neovascularization in Cathepsin K-Deficient Mice. (2012)
  • Author(s): 姜海英.
  • Organizer: 第44回日本動脈硬化学会
  • Place of Presentation: ヒルトン 福岡シーホーク(福岡県)
• [Presentation] Exploration of Mechanisms of Atherosclerotic Plaque Rupture: From A New and Simple Mouse Model of Plaque Rupture. (2012)
  • Author(s): 成憲武.
  • Organizer: 第44回日本動脈硬化学会
  • Place of Presentation: ヒルトン 福岡シーホーク(福岡県)
• [Presentation] Cysteine Protease Cathepsin K: A New Biomarker in Patients with Atrial Fibrillation. (2012)
  • Author(s): Fujita M,.
  • Organizer: 第60回日本心臓病学会学術集会
  • Place of Presentation: 石川県立音楽堂、ANAクラウンプラザ金沢、ホテル日航金沢、金沢市アートホール(石川県)
• [Presentation] Mechanisms Underlying the Impairment of Ischemia-Induced Neovascularization in Cathepsin K-Deficient Mice. (2012)
  • Author(s): Jiang HY.
  • Organizer: American Heart association. Scientific Sections 2012.
  • Place of Presentation: Los Angeles, Califonia, USA.
• [Presentation] Cathepsin K Deficiency Suppresses Characteristics of blood pressure profiles and vascular dysfunction. (2012)
  • Author(s): Cheng XW.
  • Organizer: The Korea Society of Hypertension (KSH 2012).
  • Place of Presentation: Seuol, Korea
  • Invited
• [Presentation] Cathepsins and atherosclerosis. (2012)
  • Author(s): Cheng XW.
  • Organizer: The Korea Society of Hypertension (KSH 2012).
  • Place of Presentation: Seuol, Korea
  • Invited
• [Presentation] Exercise Rescues Vascular Action in Response to Hypoxia in Aged Animal and Humans. (2012)
  • Author(s): Cheng XW.
  • Organizer: 3 rd Gwangju-Boston Cardiology Joint Symposium (GBCS).
  • Place of Presentation: Gwangju, Korea
  • Invited
• [Presentation] Progression in Cardiovascular Disease Research: Focusing on Cathepsins and Biomarkers. (2012)
  • Author(s): Cheng XW.
  • Organizer: Kyung Hee University Atherosclerosis Symposium.
  • Place of Presentation: Seoul, Korea
  • Invited
• [Presentation] Anti-Vascular Aging: Impact on Exercise and EPCs. (2012)
  • Author(s): Cheng XW.
  • Organizer: The 3rd International Symposium on the Frontiers in Cardiovascular Diseases (3rd ISFC).
  • Place of Presentation: Xiamen, China
  • Invited
• [Presentation] The Progress of Cardiovascular Disease Research: Focusing on Anti-Vascular Aging and Cathepsins. (2012)
  • Author(s): Cheng XW.
  • Organizer: Animal Pathological Research Meeting in the Laboratory Animal Center of Xi’an Jaiotong University School of Medicine.
  • Place of Presentation: Xiamen, China
  • Invited
• [Presentation] The Progress in Angiogenesis Research: Focusing on Notch1 Activation and Cathepsin K.
  • Author(s): Cheng XW.
  • Organizer: Myocardial Ischemia Symposium in Korea 2013 (MIS-Korea).
  • Place of Presentation: ソウル(韓国)
  • Invited
• [Presentation] Cathepsin K-A Classical Bone Biomarker in Cardiovascular Disease: The heart is not alone anymore.
  • Author(s): Cheng XW.
  • Organizer: The 3rd East Asia Cardiovascular International Cardiovascular Symposium.
  • Place of Presentation: 哈爾濱(中国)
  • Invited
• [Presentation] Cysteine Protease Cathepsins and Atherosclerosis-Based Cardiovascular disease.
  • Author(s): Cheng XW.
  • Organizer: The 5th Xian Experimental Medicine Symposium
  • Place of Presentation: 西安(中国)
  • Invited
• [Presentation] Exercise and Cardiovascular Medicine: from Bench to Biside: Exercise on Vascular Aging and Atherosclerosis
  • Author(s): Cheng XW.
  • Organizer: The 5th Kyung Hee Atherosclerosis Symposium
  • Place of Presentation: ソウル(韓国)
  • Invited
• [Book] 血管新生研究の最先端-血管新生研究の最先端.血管新生におけるインテグリンの役割(佐藤靖史,高倉伸幸編) (2013)
  • Author(s): 成憲武,室原豊明
  • Total Pages: 332
  • Publisher: 医薬ジャーナル社
• [Book] 血管新生研究の最先端－血管新生研究の最先端. 血管新生におけるインテグリンの役割. 佐藤靖史、高倉伸幸編. (2013)
  • Author(s): 成 憲武, 室原豊明.
  • Total Pages: 332
  • Publisher: 医薬ジャーナル社