Role of ROCK activity in cardiovascular diseases: a translational research

• Project/Area Number: 23591043
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Hiroshima University
• Principal Investigator: NOMA KENSUKE 広島大学, 原爆放射線医科学研究所, 助教 (00379893)
• Co-Investigator(Kenkyū-buntansha): HIGASHI Yukihito 広島大学, 原爆放射線医科学研究所, 教授 (40346490)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ROCK / 血管内皮機能 / 心血管障害 / 脳梗塞 / 血管機能 / eNOS / 国際情報交流 米国 / トランスレーショナルリサーチ / シグナル伝達 / 循環器・高血圧 / 発現制御 / 臨床

Research Abstract

From endothelial cellular and murine experiments, we have revealed that ROCK2, one of ROCK isoforms, could destabilize eNOS mRNA via ROCK2-mediated phosphorylation of eEF1A and binding of ROCK2 with 3'-UTR of eNOS mRNA. In addition, we have further found that ROCK2 could regulate cardiac hypertrophy via modulation of FHL2.
From clinical studies, we have revealed that leukocyte ROCK activity could reflect vascular function and could be quite a useful biomarker to predict cardiovascular events.
Therefore, we concluded from such a translational study that ROCK2 could be a promising target in patients with cardiovascular diseases and leukocyte ROCK activity could be a useful biomarker to evaluate vascular function.

Research Products

• [Journal Article] Rho-associated kinase is a predictor of a predictor of cardiovascular outcomes (2013)
  • Author(s): Kajikawa M, Noma K, Maruhashi T, Mikami S, Iwamoto Y, Iwamoto A, Matsumoto T, Hidaka T, Kihara Y, Chayama K, Nakashima A, Goto C, Liao JK, Higashi Y.
  • Journal Title: Hypertension Volume: 64 Pages: 856-864
  • Peer Reviewed
• [Journal Article] FHL2 prevents cardiac hypertrophy in mice with cardiac-specific deletion of ROCK2. (2013)
  • Author(s): Noma K, Okamoto R, Li Y, Hiroi Y, Liu PY, Taniguchi M, Ito M, Liao JK.
  • Journal Title: FASEB J. Volume: 27 Issue: 4 Pages: 1439-1449
  • DOI: 10.1096/fj.12-217018
  • Peer Reviewed
• [Journal Article] Rho-associated kinase is a predictor of a predictor of cardiovascular outcomes. (2013)
  • Author(s): Kajikawa M, Noma K, Maruhashi T, Mikami S, Iwamoto Y, Iwamoto A, Matsumoto T, Hidaka T, Kihara Y, Chayama K, Nakashima A, Goto C, Liao JK, Higashi Y.
  • Journal Title: Hypertension. Volume: 64 Issue: 4 Pages: 856-864
  • DOI: 10.1161/hypertensionaha.113.02296
  • Peer Reviewed / Open Access
• [Journal Article] Flow-Mediated Vasodilation and Anatomical Variation of the Brachial Artery (Double Brachial Artery) in Healthy Subjects and Patients with Cardiovascular Diseases. (2013)
  • Author(s): Fujii Y, Teragawa H, Soga J, Idei N, Fujimura N, Maruhashi T, Mikami S, Iwamoto Y, Hidaka T, Kihara Y, Chayama K, Noma K, Nakashima A, Goto C, Higashi Y.
  • Journal Title: Circ J Volume: 77 Pages: 1073-1080
  • NAID: 10031139013
  • Peer Reviewed
• [Journal Article] FHL2 prevents cardiac hypertrophy in mice with cardiac-specific deletion of ROCK2. (2013)
  • Author(s): Noma K, Okamoto R, Li Y, Hiroi Y, Liu PY, Taniguchi M, Ito M, Liao JK.
  • Journal Title: FASEB J Volume: 27 Pages: 1439-1449
  • Peer Reviewed
• [Journal Article] A Novel Noninvasive and Simple Method for Assessment of Endothelial Function:Enclosed Zone Flow-Mediated Vasodilation (ezFMD) Using an Oscillation Amplitude Measurement. (2013)
  • Author(s): Idei N, Ukawa T, Kajikawa M, Iwamoto Y, Fujimura N, Maruhashi T, Mikami S, Matsumoto T, Kihara Y, Chayama K, Noma K, Nakashima A, Takayanagi T, Morimoto H, Tsuji T, Higashi Y.
  • Journal Title: Circ J Volume: in press
  • Peer Reviewed
• [Journal Article] Nitroglycerine-induced Vasodilation for Assessment of Vascular Function: A Comparison with Flow-mediated Vasodilation. (2013)
  • Author(s): Maruhashi T, Soga J, Fujimura N, Idei N, Mikami S, Iwamoto Y, Kajikawa M, Matsumoto T, Hidaka T, Kihara Y, Chayama K, Noma K, Nakashima A, Goto C, Higashi Y.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: in press
  • Peer Reviewed
• [Journal Article] Mineralocorticoid Receptor Blocker Eplerenone Improves Endothelial Function and Inhibits Rho-associated Kinase Activity in Patients With Hypertension (2012)
  • Author(s): Fujimura N, Noma K, Hata T, Soga J, Hidaka T, Idei N, Fujii Y, Mikami S, Maruhashi T, Iwamoto Y, Kihara Y, Chayama K, Kato H, Liao JK, Higashi Y.
  • Journal Title: Clin Pharmacol Ther Volume: 91 Issue: 2 Pages: 289-297
  • DOI: 10.1038/clpt.2011.227
  • Peer Reviewed
• [Journal Article] Striking Crosstalk of ROCK Signaling with Endothelial Function (2012)
  • Author(s): Noma K, Kihara Y, Higashi Y.
  • Journal Title: J Cardiol Volume: 60 Pages: 1-6
  • NAID: 10031187760
  • Peer Reviewed
• [Journal Article] How to Use Ezetimibe as an Anti-Atherogenic Agent via Inhibition of Rho-Kinase (2012)
  • Author(s): Noma K, Higashi Y.
  • Journal Title: Circ J Volume: 76 Pages: 1836-1837
  • NAID: 10030504234
  • URL: https://www.jstage.jst.go.jp/browse/circj/
  • Peer Reviewed
• [Journal Article] Intima-Media Thickness of Brachial Artery, Vascular Function, and Cardiovascular Risk Factors. (2012)
  • Author(s): Iwamoto Y, Maruhash T, Fujii Y, Idei N, Fujimura N, Mikami S, Kajikawa M, Matsumoto T, Kihara Y, Chayama K, Noma K, Nakashima A, Higashi Y.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 32 Issue: 9 Pages: 2295-2303
  • DOI: 10.1161/atvbaha.112.249680
  • Peer Reviewed
• [Journal Article] Hyperbilirubinemia, Augmentation of Endothelial Function and Decrease in Oxidative Stress in Gilbert Syndrome. (2012)
  • Author(s): Maruhashi T, Soga J, Fujimura N, Idei N, Mikami S, Iwamoto Y, Kajikawa M, Matsumoto T, Kihara Y, Chayama K, Noma K, Nakashima A, Tomiyama H, Takase B, Yamashina A, Higashi Y.
  • Journal Title: Circulation Volume: 126 Issue: 5 Pages: 598-603
  • DOI: 10.1161/circulationaha.112.105775
  • Peer Reviewed
• [Journal Article] Geranylgeranylacetone, Hsp90/AMPK/eNOS/NO Pathway, and Endothelial Function in Humans. (2012)
  • Author(s): Fujimura N, Jitsuiki D, Maruhashi T, Mikami S, Iwamoto Y, Kajikawa M, Chayama K, Kihara Y, Noma K, Goto C, Higashi Y.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 32 Pages: 153-160
  • Peer Reviewed
• [Journal Article] ROCK Study Group. Rho-associated kinase activity, endothelial function, and cardiovascular risk factors (2011)
  • Author(s): Higashi Y(14人中14番目)
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31 Issue: 10 Pages: 2353-9
  • DOI: 10.1161/atvbaha.111.227892
  • Peer Reviewed
• [Journal Article] Vascular Function and Circulating Progenitor Cells in Thromboangitis Obliterans (Buerger’s Disease) and Atherosclerosis Obliterans. (2011)
  • Author(s): Idei N, Nishioka K, Soga J, Hidaka T, Hata T, Fujii Y, Fujimura N, Maruhashi T, Mikami S, Teragawa H, Kihara Y, Noma K, Chayama K, Higashi Y.
  • Journal Title: Hypertension Volume: 57 Pages: 70-78
  • Peer Reviewed
• [Journal Article] Autologous Bone-Marrow Mononuclear Cell Implantation Reduces Long-Term Major Amputation Risk in Patients with Critical Limb Ischemia: A Comparison of Atherosclerotic Peripheral Arterial Disease and Buerger's Disease. (2011)
  • Author(s): Idei N, Soga J, Hata T, Fujii Y, Mikami S, Maruhashi T, Nishioka K, Hidaka T, Kihara Y, Chowdfury M, Noma K, Taguchi A, Chayama K, Sueda T, Higashi Y.
  • Journal Title: Circ Cardiovasc Interv Volume: 4 Pages: 15-25
  • Peer Reviewed
• [Journal Article] Notch1 in Bone Marrow-derived Cells Mediates Cardiac Repair Following Myocardial Infarction. (2011)
  • Author(s): Li Y, Hiroi Y, Ngoy S, Okamoto R, Noma K, Wang CY, Wang HW, Zhou Q, Radtke F, Liao R, Liao JK.
  • Journal Title: Circulation Volume: 123 Pages: 866-876
  • Peer Reviewed
• [Journal Article] Role of Rho kinase isoforms in Murine Allergic Airway Responses. (2011)
  • Author(s): Zhu M, Liu PY, Kasahara DI, Williams AS, Verbout NG, Halayko AJ, Fedulov A, Shoji T, Williams ES, Noma K, Shore SA, Liao JK.
  • Journal Title: Eur Respir J Volume: 38 Pages: 841-850
  • Peer Reviewed
• [Journal Article] Rho-Associated Kinase (ROCK) Activity, Endothelial Function and Cardiovascular Risk Factors. (2011)
  • Author(s): Soga J, Noma K, Hata T, Hidaka T, Fujii Y, Idei N, Fujimura N, Mikami S, Maruhashi T, Kihara Y, Chayama K, MD, Kato H, Liao JK, Higashi Y.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31 Pages: 2353-2359
  • Peer Reviewed
• [Journal Article] Color Doppler Flows of Corkscrew Collaterals in Thromboangiitis Obliterans (Buerger's Disease) Using Color Duplex Ultrasonography. (2011)
  • Author(s): Fujii Y, Soga J, Hidaka T, Hata T, Idei N, Fujimura N, Mikami S, Maruhashi T, Kihara Y, Noma K, Higashi Y.
  • Journal Title: J Am Coll Cardiol Volume: 57 Pages: 2539-2539
  • Peer Reviewed
• [Journal Article] Flow-mediated vasodilation is augmented in a corkscrew collateral artery compared with that in a native artery in patients with thromboangiitis obliterans (Buerger disease). (2011)
  • Author(s): Fujii Y, Fujimura N, Mikami S, Maruhashi T, Kihara Y, Chayama K, Noma K, Higashi Y.
  • Journal Title: J Vasc Surg Volume: 54 Pages: 1689-1697
  • Peer Reviewed
• [Presentation] Destabilization of eNOS mRNA via ROCK2-mediated eEF1A1 phospohrylation (2014)
  • Author(s): 野間玄督,木原康樹,東幸仁
  • Organizer: 第3回臨床高血圧フォーラム
  • Place of Presentation: 広島,日本
• [Presentation] Role of ROCK in sustained vasoconstriction in patients with essential hypertension (2014)
  • Author(s): Noma K, Goto C, Kihara Y, Liao JK, Higashi Y.
  • Organizer: The 18^<th> International Vascular Biology Meeting (IVBM2014)
  • Place of Presentation: 京都,日本
• [Presentation] ROCK as a modulator of sustained vasoconstriction of resistance artery in patients with essential hypertension (2014)
  • Author(s): Noma K, Goto C, Kihara Y, Liao JK, Higashi Y.
  • Organizer: 第78回日本循環器学会総会・学術集会
  • Place of Presentation: 東京,日本
• [Presentation] ROCK as a Modulator of Sustained Vasoconstriction of ResistanceArtery in Patients with Essential Hypertension. (2014)
  • Author(s): Noma K, Goto C, Kihara Y, Liao JK, Higashi Y.
  • Organizer: 第78回日本循環器学会総会・学術集会.
  • Place of Presentation: 東京
• [Presentation] Role of ROCK in Sustained Arterial Vasoconstriction in Patients with Essential Hypertension. (2014)
  • Author(s): Noma K, Goto C, Kihara Y, Liao JK, Higashi Y.
  • Organizer: The 18th International Vascular Biology Meeting (IVBM 2014)
  • Place of Presentation: 京都
• [Presentation] Destabilization of eNOS mRNA via ROCK2-mediated eEF1A1 phosphorylation. (2014)
  • Author(s): 野間玄督, 木原康樹, 東 幸仁.
  • Organizer: 第3回臨床高血圧フォーラム
  • Place of Presentation: 広島
• [Presentation] ROCK Activity and Endothelial Function: Potential Candidates for Vascular and Anti-aging Biomarkers (2014)
  • Author(s): 野間玄督, 木原康樹, 東 幸仁.
  • Organizer: 第14回日本抗加齢医学会総会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] Clinical Impact of ROCK in Sustained Vasoconstriction in Patients with Essential Hypertension. (2014)
  • Author(s): Noma K, Goto C, Kihara Y, Higashi Y.
  • Organizer: 第35回日本循環制御医学会総会
  • Place of Presentation: 福岡
• [Presentation] Role of ROCK in sustained vasoconstriction of resistance artery in patients with essential hypertension (2013)
  • Author(s): Noma K, Goto C, Kihara Y, Liao JK, Higashi Y.
  • Organizer: Scientific Sessions 2013, American Heart Association
  • Place of Presentation: Dallas, USA
• [Presentation] Regulation of eNOS mRNA stability via ROCK2-mediated eEF1A1 phosphorylation (2013)
  • Author(s): 野間玄督、木原康樹、東幸仁
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 大阪,日本
• [Presentation] Regulation of eNOS mRNA stability via ROCK2-mediated eEF1A1 phosphorylation. (2013)
  • Author(s): 野間玄督、木原康樹、東幸仁
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 大阪
• [Presentation] Role of ROCK in Sustained Vasoconstriction of Resistance Artery in Patients with Essential Hypertension. (2013)
  • Author(s): Noma K, Goto C, Kihara Y, Liao JK, Higashi Y.
  • Organizer: Scientific Sessions 2013, American Heart Association.
  • Place of Presentation: Dallas, USA
• [Presentation] Clinical Evaluation of Endothelial Function and Dysfunction (2013)
  • Author(s): 野間玄督, 木原康樹, 東 幸仁.
  • Organizer: 第35回EMBC学術集会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] ROCK関連研究の新たな展開 (2012)
  • Author(s): 野間玄督,東幸仁
  • Organizer: 第41回日本心脈管作動物質学会
  • Place of Presentation: 秋田,日本
• [Presentation] ROCK関連研究の新たな展開 (2012)
  • Author(s): 野間玄督, 東幸仁
  • Organizer: 第41回日本心脈管作動物質学会(招待講演)
  • Place of Presentation: 秋田
• [Presentation] Role of ROCK in sustained vasoconstriction in patients with essential hypertension. (2012)
  • Author(s): 野間玄督, 東幸仁
  • Organizer: 第8回宮崎サイエンスキャンプ
  • Place of Presentation: 宮崎
• [Presentation] 心血管疾患におけるROCK活性:メディエーターそしてマーカーとしての役割 (2011)
  • Author(s): 野間玄督,東幸仁,木原康樹
  • Organizer: 第19回日本血管生物医学会学術集会
  • Place of Presentation: 東京,日本
• [Presentation] Leukocyte ROCK activity : a potential candidate for vascular and anti-aging biomarker (2011)
  • Author(s): 野間玄督,木原康樹,東幸仁
  • Organizer: アンチエイジングフェスタ2011
  • Place of Presentation: 大阪,日本
• [Presentation] 心血管疾患におけるROCK活性：メディエーターそしてマーカーとしての役割 (2011)
  • Author(s): 野間玄督, 東幸仁, 木原康樹
  • Organizer: 第19回日本血管生物医学会学術集会(招待講演)
  • Place of Presentation: 東京
• [Presentation] Leukocyte ROCK Activity: a Potential Candidate for Vascular and Anti-aging Biomarker. (2011)
  • Author(s): 野間玄督, 木原康樹, 東幸仁
  • Organizer: アンチエイジングフェスタ2011
  • Place of Presentation: 大阪
• [Presentation] Regulation of eNOS mRNA stability vie ROCK2-mediated phosphorylation of eEF1A
  • Author(s): 野間玄督，廣井透雄，James K. Liao、，東 幸仁
  • Organizer: 第9回宮崎サイエンスキャンプ
  • Place of Presentation: 宮崎
  • Invited
• [Book] ICU看護実践ハンドブック (2013)
  • Author(s): 野間玄督，東 幸仁
  • Total Pages: 4
  • Publisher: 羊土社
• [Book] 糖尿病と酸化ストレス (2011)
  • Author(s): 野間玄督, 東幸仁
  • Total Pages: 5
  • Publisher: メディカルレビュー社