血管内皮細胞障害におけるミトコンドリア機能の役割検討と臨床評価、新治療の探索

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25461086
• Research Institution: Kumamoto University
• Principal Investigator: 杉山 正悟 熊本大学, 生命科学研究部, 非常勤講師 (90274711)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 血管内皮機能 / ミトコンドリア / 動脈硬化 / 冠動脈疾患 / Polyvascular disease / 心不全

Outline of Annual Research Achievements

［背景］AMP-activated protein kinase (AMPK)は血管内皮細胞やマクロファージにおいて、抗炎症効果、血管内皮機能改善効果を持つことが報告されている。アンギオテンシンⅡ1型受容体拮抗薬 (ARB)であるテルミサルタン(Telmi)は、これまでの臨床研究や基礎研究において心血管系に有益な効果を持つことが報告されている。Telmiを用いて、AMPK活性化を介した心血管系への有益な効果について検証した。
［方法］培養ヒト冠動脈内皮細胞（HCAECs）に対してTelmiを投与し、ミトコンドリア機能や血管内皮機能に対する効果とAMPK活性効果との関連について検証を行った。糖尿病モデルマウスを用いてTelmiによる血管内皮機能への影響を検証した。高血圧患者において、Telmiによる血管内皮機能への影響を検証した。
［結果］HCAECsにおいて、Telmiはミトコンドリア機能を増強していた。他のARBではそのような効果は認められなかった。Telmi投与により細胞老化抑制効果、抗アポトーシス効果、血管新生増強効果が認められた。HCAECsにおいてTelmiはAMPKを活性化しており、Telmiによるミトコンドリア機能増強効果や抗老化・抗アポトーシス作用は、AMPKの薬理学的・遺伝的阻害により打ち消された。糖尿病モデルマウスにおいて、Telmiは高脂肪食由来の血管内皮機能障害を改善しており、マウスの大動脈ではAMPKの活性化が認められた。angiotensin converting enzyme (ACE)阻害薬もしくはTelmi以外のARBで治療中の高血圧患者において、Telmiへの薬剤変更により血管内皮機能の改善が認められた。
［考察］TelmiはAMPKを活性化することにより、ミトコンドリア機能を亢進し心血管系に保護的な作用を示すと考えられる。
［結論］AMPK活性化を介したミトコンドリア機能改善が心血管系に保護的な効果をもたらすことが期待できる。

Research Products

• [Journal Article] Advanced peripheral microvascular endothelial dysfunction and polyvascular disease in patients with high cardiovascular risk. (2016)
  • Author(s): Maeda H, Sugiyama S, Jinnouchi H, Matsuzawa Y, Fujisue K, Hirata Y, Kurokawa H, Ohba K, Matsubara J, Nozaki T, Konishi M, Akiyama E, Sugamura K, Yamamoto E, Sumida H, Ogawa H.
  • Journal Title: J Cardiol. Volume: 67 Pages: 455-462
  • DOI: 10.1016/j.jjcc.2015.07.003.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Low-Normal Serum Sodium and Heart Failure-Related Events in Patients With Heart Failure With Preserved Left Ventricular Ejection Fraction. (2016)
  • Author(s): Kusaka H, Sugiyama S, Yamamoto E, Akiyama E, Matsuzawa Y, Hirata Y, Fujisue K, Kurokawa H, Matsubara J, Sugamura K, Maeda H, Jinnouchi H, Matsui K, Ogawa H.
  • Journal Title: Circ J. Volume: 80 Pages: 411-417
  • DOI: 10.1253/circj.CJ-15-0878
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Telmisartan enhances mitochondrial activity and alters cellular functions in human coronary artery endothelial cells via AMP-activated protein kinase pathway. (2015)
  • Author(s): Kurokawa H, Sugiyama S, Nozaki T, Sugamura K, Toyama K, Matsubara J, Fujisue K, Ohba K, Maeda H, Konishi M, Akiyama E, Sumida H, Izumiya Y, Yasuda O, Kim-Mitsuyama S, Ogawa H.
  • Journal Title: Atherosclerosis Volume: 239 Pages: 275-385
  • DOI: 10.1016/j.atherosclerosis.2015.01.037.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Significance of low plasma levels of brain-derived neurotrophic factor in patients with heart failure. (2015)
  • Author(s): Takashio S, Sugiyama S, Yamamuro M, Takahama H, Hayashi T, Sugano Y, Izumiya Y, Hokimoto S, Minamino N, Yasuda S, Anzai T, Ogawa H.
  • Journal Title: Am J Cardiol. Volume: 116 Pages: 243-249
  • DOI: 10.1016/j.amjcard.2015.04.018.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Prognostic Significance of Peripheral Microvascular Endothelial Dysfunction in Heart Failure With Reduced Left Ventricular Ejection Fraction. (2015)
  • Author(s): Fujisue K, Sugiyama S, Matsuzawa Y, Akiyama E, Sugamura K, Matsubara J, Kurokawa H, Maeda H, Hirata Y, Kusaka H, Yamamoto E, Iwashita S, Sumida H, Sakamoto K, Tsujita K, Kaikita K, Hokimoto S, Matsui K, Ogawa H.
  • Journal Title: Circ J. Volume: 79 Pages: 2623-2631
  • DOI: 10.1253/circj.CJ-15-0671.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Reactive hyperemia peripheral arterial tonometry（RH-PAT））検査を臨床診療に活かす (2015)
  • Author(s): 杉山 正悟
  • Journal Title: 循環器内科 Volume: 78 Pages: 246-255
• [Presentation] Dual Lipid-Lowering with Ezetimibe/Statin as a Promising Anti-Atherosclerotic Strategy (2016)
  • Author(s): Tsujita K, Sugiyama S, Shimomura H, Yamanaga K, Tsunoda R, Morikami Y, Matsuyama K, Ohshima S, Oka H, Nakao K, Nakamura S, Ishihara M, Matsui K, Sakaino N, Yamamoto N, Nakamura N, Koide S, Fujimoto K, Kaikita K, Hokimoto S, Ogawa H.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Colchicine Improved Survival, Left Ventricular Remodeling, and Chronic Cardiac Function after Acute Myocardial Infarction (2016)
  • Author(s): Fujisue K, Sugiyama S, Sugamura K, Kurokawa H, Matsubara J, Kaikita K, Ogawa H.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] The Clinical Significance and Novel Mechanism of Reactive Oxygen Species (ROS) in Heart Failure with Preserved Ejection Fraction (HFpEF) (2016)
  • Author(s): Hirata Y, Yamamoto E, Tokitsu T, Fujisue K, Sugamura K, Sakamoto K, Tsujita K, Kaikita K, Hokimoto S, Sugiyama S, Ogawa H.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Risk Stratification of Heart Failure (HF) with Preserved Ejection Fraction (HFpEF) Patients by Using Ankle-Brachial Index (ABI) Devices (2016)
  • Author(s): Tokitsu T, Yamamoto E, Hirata Y, Kusaka H, Fujisue K, Sugamura K, Yamamuro M, Kaikita K, Hokimoto S, Sugiyama S, Ogawa H.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Clinical Significance of Pulse Pressure (PP) in Patients with Heart Failure (HF) with Preserved Left Ventricular (LV) Ejection Fraction (HFpEF) (2016)
  • Author(s): Tokitsu T, Yamamoto E, Hirata Y, Fujisue K, Kusaka H, Sugamura K, Yamamuro M, Kaikita K, Hokimoto S, Sugiyama S, Ogawa H.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Impact of Statin-Ezetimibe Combination on Coronary Atheroma Progression/Regression in Patients with and without Statin Pretreatment― Subanalysis of PRECISE-IVUS Trial ― (2016)
  • Author(s): Tsujita K, Yamanaga K, Sugiyama S, Shimomura H, Yamashita T, Sakamoto K, Nakao K, Nakamura S, Ishihara M, Matsui K, Yamamoto N, Koide S, Matsumura T, Fujimoto K, Tsunoda R, Morikami Y, Matsuyama K, Ohshima S, Kaikita K, Hokimoto S, Ogawa H.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] The Usefulness of Digital Assessment of Peripheral Vascular Endothelial Function for the Risk Stratification in Patients with Essential Hypertension (HT) (2016)
  • Author(s): Yamamoto E, Sugiyama S, Matsuzawa Y, Hirata Y, Tokistu T, Fujisue K, Akiyama E, Sugamura K, Maeda H, Ogawa H.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] The Comparison of Statin Monotherapy and Statin-Ezetimibe Combined Therapy to Reduce LDL-C under 70mg/dl in Patients with Coronary Artery Disease (2016)
  • Author(s): Yamanaga K, Tsujita K, Sugiyama S, Sumida H, Shimomura H, Komura N, Sakamoto K, Nakao K, Nakamura S, Ishihara M, Matsui K, Nakamura N, Yamamoto N, Koide S, Tsunoda R, Morikami Y, Matsuyama K, Ohshima S, Kaikita K, Hokimoto S, Ogawa H.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Predictive Value of Endothelial Function for the Recurrence of Atrial Fibrillation after Catheter Ablation (2016)
  • Author(s): Kanazawa H, Yamabe H, Sugiyama S, Iwashita S, Ito M, Kaneko S, Ogawa H.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Primary Prevention for Silent Myocardial Infarction and Acute Myocardial Infarction in Diabetic Patients (2016)
  • Author(s): Soejima H, Morimoto T, Okada S, Nakayama M, Sakuma M, Uemura S, Kanauchi M, Doi N, Jinnouchi H, Sugiyama S, Waki M, Saito Y, Ogawa H.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Association between Circulating Leukocyte Subtype Counts and Peripheral Endothelial Dysfunction (ED) in Patients with Coronary Artery Disease (CAD) (2016)
  • Author(s): Yamamoto E, Hirata Y, Tokitsu T, Fujisue K, Sugamura K, Tsujita K, Hokimoto S, Sugiyama S, Ogawa H.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Blood Pressure Control in Diabetic Patients is Most Effective Between Ages 65 to 75 for Prevention of Atherosclerotic Events (2015)
  • Author(s): Soejima H, Morimoto T, Okada S, Sakuma M, Nakayama M, Uemura S, Masao K, Doi N, Jinnouchi H, Sugiyama S, Waki M, Saito Y, Ogawa H.
  • Organizer: American Heart Association Scientific Session
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2015-11-07 – 2105-11-11
• [Presentation] Peripheral Microvascular Endothelial Dysfunction Improves Risk Determination of Seattle Heart Failure Model in Heart Failure with Reduced Left Ventricular Ejection Fraction (2015)
  • Author(s): Fujisue K, Sugiyama S, Akiyama E, Matsuzawa Y, Sugamura K, Matsubara J, Kurokawa H, Maeda H, Hirata Y, Kusaka H, Yamamoto E, Iwashita S, Sumida H, Tsujita K, Sakamoto K, Kaikita K, Hokimoto S, Matsui K, Ogawa H.
  • Organizer: American Heart Association Scientific Session
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2015-11-07 – 2015-11-11
• [Presentation] The Impact of Statin-Ezetimibe Combination Therapy in Patients With Decreased Cholesterol Absorption Ability (2015)
  • Author(s): Yamanaga K, Tsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Komura N, Sakamoto K, Oka H, Nakao K, Nakamura S, Ishihara M, Matsui K, Skaino N, Nakamura N, Yamamoto N, Koide S, Matsumura T, Fujimoto K, Tsunoda R, Morikami Y, Matsuyama K, Oshima S, KKaikita K, Hokimoto S, Ogawa H.
  • Organizer: American Heart Association Scientific Session
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2015-11-07 – 2015-11-11
• [Presentation] Impact of Statin-Ezetimibe Combination on Coronary Atheroma Progression/Regression in Patients With and Without Prior Statin Therapy - Subanalysis of PRECISE-IVUS Trial (2015)
  • Author(s): Tsujita K, Yamanaga K, Sugiyama S, Shimomura H, Yamashita T, Sakamoto K, Nakao K, Nakamura S, Ishihara M, Matsui K, Yamamoto N, Koide S, Matsumura T, Fujimoto K, Tsunoda R, Morikami Y, Matsuyama K, Oshima S, Kaikita K, Hokimoto S, Ogawa H.
  • Organizer: American Heart Association Scientific Session
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2015-11-07 – 2015-11-11
• [Presentation] Digital Assessment of Peripheral Vascular Endothelial Function is Useful for the Risk Stratification in Patients With Hypertension (2015)
  • Author(s): Yamamoto E, Sugiyama S, Matsuzawa Y, Hirata Y, Akiyama E, Fujisue K, Tokitsu T, Sugamura K, Kaikita K, Hokimoto S, Ogawa H.
  • Organizer: American Heart Association Scientific Session
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2015-11-07 – 2015-11-11
• [Presentation] Olmesartan Improves Not Only Vascular Endothelial Dysfunction but Cardiac Diastolic Dysfunction in Hypertensive Heart Failure With Preserved Ejection Fraction - ORION Study (2015)
  • Author(s): Yamamoto E, Ohba K, Hirata Y, Tokitsu T, Sugamura K, Hokimoto S, Sugiyama S, Ogawa H.
  • Organizer: American Heart Association Scientific Session
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2015-11-07 – 2015-11-11
• [Presentation] Predictive Value of Endothelial Function for the Recurrence of Atrial Fibrillation After Catheter Ablation (2015)
  • Author(s): Kanazawa H, Yamabe H, Sugiyama S, Iwashita S, Hoshiyama T, Ito M, Kaneko S Ogawa H.
  • Organizer: American Heart Association Scientific Session
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2015-11-07 – 2015-11-11
• [Presentation] The Clinical Significance of Pulse Pressure in Patients With Heart Failure With Preserved Ejection Fraction (2015)
  • Author(s): Tokitsu T, Yamamoto E, Hirata Y, Fujisue K, Sugamura K, Yamamuro M, Kaikita K, Hokimoto S, Sugiyama S, Ogawa H.
  • Organizer: American Heart Association Scientific Session
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2015-11-07 – 2015-11-11