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

2014 Fiscal Year Research-status 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 / 老化 / ATP産生 / 酸化ストレス / 心血管イベント

Outline of Annual Research Achievements

血管内皮機能におけるミトコンドリア機能の関与について細胞レベルでの検討を行った。
培養血管内皮細胞において、各腫アンギオテンシンType-1受容体拮抗薬(ARB)のミトコンドリア機能に対する効果をmitochondrial reductase活性とATP産生能で検討し、テルミサルタンがヒト血管内皮細胞ミトコンドリア機能を増強することが明らかとなった。テルミサルタンは、AMPKを活性化しeNOSの活性化リン酸化を亢進する事でミトコンドリア機能を活性化していることを示した。テルミサルタンは、酸化ストレスによる血管内皮細胞apoptosisを抑制し、酸化ストレスによる老化促進を減弱させた。テルミサルタンは、血管内皮細胞においてmitochondria biogenesisを促進する因子(TFAM, NRF1, SIRT-1, SIRT-3)の発現を亢進させた。(Atherosclerosis; 2015, 239:375-385)
臨床研究において、冠動脈リスクを有するCKD患者で末梢微小血管内皮機能は低下しており、この低下した血管内皮細胞機能が将来の心血管イベント予測の独立した寄与因子で有ることを明らかにした（Int J Card. 2014;173:481-486）また、横浜市立大学との共同研究で整形外科領域下肢手術後に生じる深部静脈血栓症の発症予測にreactive hyperemia peripheral arterial tonometry で評価した末梢微小血管内皮機能が有意で独立した予測因子になる事を明らかにした（Circ J. 2014;78:1723-1732）

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

培養細胞を使用した血管内皮細胞におけるミトコンドリア機能修飾を検討した。
ヒト血中白血球のミトコンドリア機能評価を実施した。
培養内皮細胞においてミトコンドリア機能と細胞機能の連関を検討できている。
臨床研究の成果が発表できている。

Strategy for Future Research Activity

マウスモデルにおいて急性心筋梗塞を作成し、その際に起こる心筋障害を軽減する治療をミトコンドリア機能修飾の面から検討する。
培養血管内皮細胞において細胞機能とミトコンドリア機能の変化のメカニズムを詳細に検討する。
臨床研究においてヒト血管内皮機能障害を改善出来る薬剤治療を検索する。

Research Products

• [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] Decreased plasma levels of active glucagon-like peptide-1 in coronary artery disease. (2015)
  • Author(s): Akiyama E, Sugiyama S, Matsubara J, Kurokawa H, Konishi M, Nozaki T, Ohba K, Fujisue K, Maeda H, Sakamoto K, Sugamura K, Sumida H, Jinnouchi H, Sakamaki K, Morita S, Kimura K, Umemura S, Ogawa H.
  • Journal Title: J Am Coll Cardiol. Volume: 65 Pages: 754-755
  • DOI: 10.1016/j.jacc.2014.11.043
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Reactive oxygen metabolites are closely associated with the diagnosis and prognosis of coronary artery disease. (2015)
  • Author(s): Hirata Y, Yamamoto E, Tokitsu T, Kusaka H, Fujisue K, Kurokawa H, Sugamura K, Maeda H, Tsujita K, Kaikita K, Hokimoto S, Sugiyama S, Ogawa H.
  • Journal Title: J Am Heart Assoc. Volume: 4 Pages: e001451
  • DOI: 10.1161/JAHA.114.001451
  • Peer Reviewed / Open Access
• [Journal Article] Plaque REgression with Cholesterol absorption Inhibitor or Synthesis inhibitor Evaluated by IntraVascular UltraSound (PRECISE-IVUS Trial): Study protocol for a randomized controlled trial. (2015)
  • Author(s): Tsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Yamanaga K, Komura N, Sakamoto K, Ono T, Oka H, Nakao K, Nakamura S, Ishihara M, Matsui K, Sakaino N, Nakamura N, Yamamoto N, Koide S, Matsumura T, Fujimoto K, Tsunoda R, Morikami Y, Matsuyama K, Oshima S, Kaikita K, Hokimoto S, Ogawa H
  • Journal Title: J Cardiol. Volume: 65 Pages: S0914-5087
  • DOI: 10.1016/j.jjcc.2014.12.011
  • Peer Reviewed
• [Journal Article] Reactive oxidative metabolites are associated with the severity of heart failure and predict future cardiovascular events in heart failure with preserved left ventricular ejection fraction. (2015)
  • Author(s): Hirata Y, Yamamoto E, Tokitsu T, Kusaka H, Fujisue K, Kurokawa H, Sugamura K, Maeda H, Tsujita K, Yamamuro M, Kaikita K, Hokimoto S, Sugiyama S, Ogawa H.
  • Journal Title: Int J Cardiol. Volume: 179 Pages: 305-308
  • DOI: 10.1016/j.ijcard.2014.11.018
  • Peer Reviewed
• [Journal Article] Effect of a hydrophilic and a hydrophobic statin on cardiac salvage after ST-elevated acute myocardial infarction - a pilot study. (2014)
  • Author(s): Chitose T, Sugiyama S, Sakamoto K, Shimomura H, Yamashita T, Hokamaki J, Tsunoda R, Shiraishi S, Yamashita Y, Ogawa H.
  • Journal Title: Atherosclerosis Volume: 237 Pages: 251-258
  • DOI: 10.1016/j.atherosclerosis.2014.08.053
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Differences between rosuvastatin and atorvastatin in lipid-lowering action and effect on glucose metabolism in Japanese hypercholesterolemic patients with concurrent diabetes. Lipid-lowering with highly potent statins in hyperlipidemia with type 2 diabetes patients (LISTEN) study. (2014)
  • Author(s): Ogawa H, Matsui K, Saito Y, Sugiyama S, Jinnouchi H, Sugawara M, Masuda I, Mori H, Waki M, Yoshiyama M, Watada H.
  • Journal Title: Circ J Volume: 78 Pages: 2512-2515
  • Peer Reviewed / Open Access
• [Journal Article] Incremental prognostic significance of the elevated levels of pentraxin 3 in patients with heart failure with normal left ventricular ejection fraction. (2014)
  • Author(s): Matsubara J, Sugiyama S, Nozaki T, Akiyama E, Matsuzawa Y, Kurokawa H, Maeda H, Fujisue K, Sugamura K, Yamamoto E, Matsui K, Jinnouchi H, Ogawa H.
  • Journal Title: J Am Heart Assoc. Volume: 3 Pages: e000928
  • DOI: 10.1161/JAHA.114.000928
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical features and prognosis of patients with coronary spasm-induced non-ST-segment elevation acute coronary syndrome. (2014)
  • Author(s): Nakayama N, Kaikita K, Fukunaga T, Matsuzawa Y, Sato K, Horio E, Yoshimura H, Mizobe M, Takashio S, Tsujita K, Kojima S, Tayama S, Hokimoto S, Sakamoto T, Nakao K, Sugiyama S, Kimura K, Ogawa H.
  • Journal Title: J Am Heart Assoc. Volume: 3 Pages: e000795
  • DOI: 10.1161/JAHA.114.000795
  • Peer Reviewed / Open Access
• [Journal Article] Utility of noninvasive endothelial function test for prediction of deep vein thrombosis after total hip or knee arthroplasty. (2014)
  • Author(s): Suzuki H, Matsuzawa Y, Konishi M, Akiyama E, Takano K, Nakayama N, Kataoka S, Ebina T, Kosuge M, Hibi K, Tsukahara K, Iwahashi N, Endo M, Maejima N, Shinohara K, Taki N, Mitsugi N, Taguri M, Sugiyama S, Ogawa H, Umemura S, Kimura K.
  • Journal Title: Circ J Volume: 78 Pages: 1723-1732
  • Peer Reviewed / Open Access
• [Journal Article] Endothelial function and cardiovascular events in chronic kidney disease. (2014)
  • Author(s): Hirata Y, Sugiyama S, Yamamoto E, Matsuzawa Y, Akiyama E, Kusaka H, Fujisue K, Kurokawa H, Matsubara J, Sugamura K, Maeda H, Iwashita S, Jinnouchi H, Matsui K, Ogawa H.
  • Journal Title: Int J Cardiol. Volume: 173 Pages: 481-486
  • DOI: 10.1016/j.ijcard.2014.03.085
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Correlation between extent of myocardial fibrosis assessed by cardiac magnetic resonance and cardiac troponin T release in patients with nonischemic heart failure. (2014)
  • Author(s): Takashio S, Yamamuro M, Uemura T, Utsunomiya D, Morita K, Izumiya Y, Sugiyama S, Kojima S, Yamamoto E, Tsujita K, Tanaka T, Tayama S, Kaikita K, Hokimoto S, Yasuda O, Yamashita Y, Ogawa H.
  • Journal Title: Am J Cardiol. Volume: 113 Pages: 1697-1704
  • DOI: 10.1016/j.amjcard.2014.02.029
  • Peer Reviewed / Open Access
• [Journal Article] tatins combined with exercise are associated with the increased renal function mediated by high-molecular-weight adiponectin in coronary artery disease patients. (2014)
  • Author(s): Toyama K, Sugiyama S, Oka H, Iwasaki Y, Sumida H, Tanaka T, Tayama S, Jinnouchi H, Ogawa H.
  • Journal Title: J Cardiol. Volume: 64 Pages: 91-97
  • DOI: 10.1016/j.jjcc.2013.11.018
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Reactive hyperemia peripheral arterial tonometry (RH-PAT)による血管内皮機能 (2014)
  • Author(s): 杉山正悟
  • Journal Title: 心臓 Volume: 46 Pages: 1330-1335
• [Journal Article] Insulin supersensitivity and normoinsulinaemic hypoglycaemia in uncontrolled type 2 diabetes mellitus: clinical usefulness of 3 h assessment in the 75 g oral glucose tolerance test. (2014)
  • Author(s): Sugiyama S, Jinnouchi H, Hieshima K, Jinnouchi T.
  • Journal Title: BMJ Case Rep. Volume: 8 Pages: bcr2013201908
  • DOI: 10.1136/bcr-2013-201908
  • Peer Reviewed
• [Presentation] Elevated Plasma levels of Neutral Endpeptidase in Hypertension Patients Treated with Angiotensin Converting Enzyme Inhibitors (2014)
  • Author(s): Sugamura K, Sugiyama S, Fujisue K, Hirata Y, Kurokawa H, Yamamoto E, Tsujita K, Kaikita K, Hokimoto S, Ogawa H.
  • Organizer: American Heart Association Scientific Sessions 2014
  • Place of Presentation: McCormick Place, Chicago, Illinois, USA
  • Year and Date: 2014-11-19 – 2014-11-19
• [Presentation] Incremental Prognostic Significance of Peripheral Endothelial Dysfunction in Heart Failure With Reduced Left Ventricular Ejection Fraction (2014)
  • 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, Tsujita K, Kaikita K, Hokimoto S, Matsui K, Ogawa H
  • Organizer: American Heart Association Scientific Sessions 2014
  • Place of Presentation: McCormick Place, Chicago, Illinois, USA
  • Year and Date: 2014-11-17 – 2014-11-17
• [Presentation] Telmisartan, a Clinically Available Anti-hypertensive Medicine, Enhances Mitochondrial Function and Improves Endothelial Dysfunction through the AMPK Pathway (2014)
  • Author(s): Kurokawa H, Sugiyama S, Nozaki T, Sugamura K, Toyama K, Matsubara J, Fujisue K, Ohba K, Maeda H, Yamamoto E, Tsujita K, Kaikita K, Hokimoto S, Ogawa H.
  • Organizer: American Heart Association Scientific Sessions 2014
  • Place of Presentation: McCormick Place, Chicago, Illinois, USA
  • Year and Date: 2014-11-17 – 2014-11-17
• [Presentation] Dipeptidyl-Peptidase-4 Inhibitor, Des-Fluoro-Sitagliptin, Prevented the Progression of Established Atheromatous Plaques in ApoE Deficient Mice - Possible Involvement of AMP-Activated Protein Kinase Pathway – (2014)
  • Author(s): Kurokawa H, Sugiyama S, Sugamura K, Matsubara J, Fujisue K, Maeda H, Yamamoto E, Tsujita K, Kaikita K, Hokimoto S, Ogawa H.
  • Organizer: American Heart Association Scientific Sessions 2014
  • Place of Presentation: McCormick Place, Chicago, Illinois, USA
  • Year and Date: 2014-11-17 – 2014-11-17
• [Presentation] 正常冠動脈における内皮依存性冠血流量増加反応と血小板機能との関連性 (2014)
  • Author(s): 藤末 昂一郎,杉山 正悟、菅村 公一、大庭 圭介、海北 幸一、黒川 博文、前田 洋典、松原 純一、角田 等、山本 英一郎、山室 恵、田中 朋子、辻田 賢一、坂本 憲治、掃本 誠治、小川 久雄
  • Organizer: 第62回日本心臓病学会学術集会
  • Place of Presentation: 仙台市民会館、仙台市、宮城県
  • Year and Date: 2014-09-26 – 2014-09-26
• [Presentation] 血管内皮機能検査で心血管リスクを評価する (2014)
  • Author(s): 杉山正悟
  • Organizer: 第46回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 京王プラザホテル、西新宿、東京
  • Year and Date: 2014-07-11 – 2014-07-11
  • Invited