Clinical significance of cholesterol uptake capacity, a novel assay of high-density lipoprotein function, in coronary artery disease

• Project/Area Number: 15K09121
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kobe University
• Principal Investigator: Tatsuro Ishida 神戸大学, 医学研究科, 特命教授 (00379413)
• Co-Investigator(Kenkyū-buntansha): 杜 隆嗣 神戸大学, 医学研究科, 特命准教授 (50379418) ; 平田 健一 神戸大学, 医学研究科, 教授 (20283880)
• Co-Investigator(Renkei-kenkyūsha): SHINKE TOSHIRO 神戸大学, 医学部附属病院, 准教授 (60379419)
• Research Collaborator: SHINOHARA MASAKAZU 神戸大学, 大学院医学研究科, 准教授 (80437483)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 高比重リポ蛋白 / コレステロール逆転送 / 動脈硬化 / 冠動脈疾患 / 脂質異常症 / HDL / エイコサペンタエン酸 / コレステロール / 逆転送 / オメガ3系多価不飽和脂肪酸 / リポタンパク質 / 高比重リポタンパク質 / コレステロール引き抜き / 脂質代謝異常 / 循環器

Outline of Final Research Achievements

We established a new method to evaluate the efficiency of HDL-induced cholesterol efflux from macrophages “cholesterol uptake capacity (CUC)” using apoB-depleted serum, fluorescently labeled cholesterol, and immobilized anti-apolipoprotein A1 antibody. When we measured CUC in patients with coronary artery disease, CUC declined with myeloperoxidase-mediated oxidation of HDL, and correlated inversely with requirement of revascularization. Multivariable analysis adjusted for traditional coronary risk factors including HDL-C showed that only CUC remained significant. Furthermore, CUC was lower in patients with lipidic plaque than that in those without lipidic plaque, and inversely associated with the lipid index in these patients. CUC was also inversely associated with Macrophage grade. CUC is an alternative measure of HDL functionality and may be a substitute for cholesterol efflux capacity and applicable for assessing CVD risk.

Research Products

• [Journal Article] Eicosapentaenoic Acid-Enriched High-Density Lipoproteins Exhibit Anti-Atherogenic Properties (2018)
  • Author(s): 6.Tanaka N, Irino Y, Shinohara M, Tsuda S, Mori T, Nagao M, Oshita T, Mori K, Hara T, Toh R, Ishida T, Hirata K
  • Journal Title: Circulation Journal Volume: 82 Issue: 2 Pages: 596-601
  • DOI: 10.1253/circj.CJ-17-0294
  • NAID: 130006321869
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B4 pathway by high-density lipoprotein in macrophages (2017)
  • Author(s): Tsuda Shigeyasu、Shinohara Masakazu、Oshita Toshihiko、Nagao Manabu、Tanaka Nobuaki、Mori Takeshige、Hara Tetsuya、Irino Yasuhiro、Toh Ryuji、Ishida Tatsuro、Hirata Ken-ichi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 12989-12989
  • DOI: 10.1038/s41598-017-13154-0
  • NAID: 120006373799
  • Peer Reviewed / Open Access
• [Journal Article] High-density lipoprotein protects cardiomyocytes from oxidative stress via the PI3K/mTOR signaling pathway (2017)
  • Author(s): Nagao Manabu、Toh Ryuji、Irino Yasuhiro、Nakajima Hideto、Oshita Toshihiko、Tsuda Shigeyasu、Hara Tetsuya、Shinohara Masakazu、Ishida Tatsuro、Hirata Ken-ichi
  • Journal Title: FEBS Open Bio Volume: 7 Issue: 9 Pages: 1402-1409
  • DOI: 10.1002/2211-5463.12279
  • NAID: 120006373788
  • Peer Reviewed
• [Journal Article] The impact of serum trans fatty acids concentration on plaque vulnerability in patients with coronary artery disease: Assessment via optical coherence tomography (2017)
  • Author(s): Nagasawa Yoshinori、Shinke Toshiro、Toh Ryuji、Ishida Tatsuro、Otake Hiromasa、Takaya Tomofumi、Sugiyama Daisuke、Terashita Daisuke、Tahara Natsuko、Shinkura Yuto、Uzu Kenzo、Kashiwagi Daiji、Kuroda Koji、Nagano Yuichiro、Yamamoto Hiroyuki、Yanaka Kenichi、Tsukiyama Yoshiro、Hirata Ken-ichi
  • Journal Title: Atherosclerosis Volume: 265 Pages: 312-317
  • DOI: 10.1016/j.atherosclerosis.2017.06.922
  • NAID: 120006377646
  • Peer Reviewed
• [Journal Article] Cholesterol Uptake Capacity: A New Measure of High-Density Lipoprotein Functionality for Coronary Risk Assessment. (2017)
  • Author(s): Harada A, Toh R, Murakami K, Kiriyama M, Yoshikawa K, Miwa K, Kubo T, Irino Y, Tanaka N, Nishimura K, Ishida T, Hirata K.
  • Journal Title: Journal of Applied Laboratory Medicine. Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Excessive intake of trans fatty acid accelerates atherosclerosis through promoting inflammation and oxidative stress in a mouse model of hyperlipidemia. (2017)
  • Author(s): Monguchi T, Hara T, Hasokawa M, Nakajima H, Mori K, Toh R, Irino Y, Ishida T, Hirata KI, Shinohara M
  • Journal Title: J Cardiol Volume: 印刷中 Issue: 2 Pages: 121-127
  • DOI: 10.1016/j.jjcc.2016.12.012
  • Peer Reviewed
• [Journal Article] Enhanced Impact of Cholesterol Absorption Marker on New Atherosclerotic Lesion Progression After Coronary Intervention During Statin Therapy (2017)
  • Author(s): Mori K, Ishida T, Tsuda S, Oshita T, Shinohara M, Hara T, Irino Y, Toh R, Hirata KI.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 2 Pages: 123-132
  • DOI: 10.5551/jat.32615
  • NAID: 130005306526
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] HDLの抗炎症能の分子機序と評価方法 (2016)
  • Author(s): 田中伸明,石田達郎.
  • Journal Title: 臨床病理 Volume: 64 Pages: 49-56
• [Journal Article] 高HDL-C血症 (2016)
  • Author(s): 篠原正和, 石田達郎
  • Journal Title: Medical Practice Volume: 33 Pages: 575-580
• [Journal Article] HDLの抗炎症能の分子機序と評価方法. (2016)
  • Author(s): 田中伸明、石田達郎
  • Journal Title: 臨床病理 Volume: 64 Pages: 49-56
• [Journal Article] 家族性低HDLコレステロール血症の分子機構 (2015)
  • Author(s): 原哲也, 石田達郎
  • Journal Title: 臨床病理. Volume: 33 Pages: 57-60
• [Journal Article] LDL/HDLコレステロールを標的とした動脈硬化症の新しい治療ストラテジー. 機能不全HDLに対する治療戦略. (2015)
  • Author(s): 入野康宏, 石田達郎, 杜隆嗣.
  • Journal Title: 血管医学 Volume: 16 Pages: 53-60
• [Presentation] Identification of Determinants of Cholesterol Uptake Capacity, a Novel Indicator for HDL Functionality (2018)
  • Author(s): Oshita T, Toh R, Ishida T, et al.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Relationships between Cholesterol Uptake Capacity, a Novel Indicator for HDL Functionality, and Morphologic Features of Coronary Plaque (2018)
  • Author(s): Oshita T, Toh R, Ishida T, et al.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Phospholipid Composition of Reconstitute High Density Lipoproteins Affects their Anti-inflammatory Effects (2018)
  • Author(s): Okano M, Irino Y, Ishida T, et al.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Inverse Association Between HDL Cholesterol Uptake Capacity And Coronary Atherosclerotic Burden: OCT-based Observation Study (2017)
  • Author(s): Toshihiko Oshita, Ryuji Toh, Amane Harada, Katsuhiro Murakami, Maria Kiriyama, Keiko Yoshikawa, Keiko Miwa, Kenta Mori, Yasuhiro Irino, Hiromasa Otake, Toshiro Shinke, Tatsuro Ishida, Ken-ichi Hirata
  • Organizer: 第81回 日本循環器学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
• [Presentation] Clinical and Practical Assessment of Dysfunctional HDL in Cardiovascular Risk Stratification (2017)
  • Author(s): Tatsuro Ishida, Ryuji Toh, Hiromasa Otake, Toshiro Shinke, Amane Harada, Ken-ichi Hirata
  • Organizer: 第81回 日本循環器学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
• [Presentation] Impaired HDL-cholesterol uptake capacity which measure HDL functionality may associate with target lesion revascularization through provoking neoatherosclerosis formation after stenting (2017)
  • Author(s): 永野雄一朗、大竹寛雅 、入野 康宏、鳥羽 敬義、高橋 八大 、寺下大輔 、黒田浩史、宇津賢三、田原奈津子 、新倉悠人、長澤圭典、築山義朗、谷仲謙一、山本裕之、新家俊郎、原田周、村上克洋、石田達郎、杜隆嗣、平田健一
  • Organizer: 第81回 日本循環器学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
• [Presentation] Association of Coronary Lipidic Plaque Burden with Impairment of Cholesterol Uptake Capacity, a Novel Indicator for HDL Functionality: OCT-based Observation Study (2017)
  • Author(s): Oshita T, Toh R, Ishida T, et al.
  • Organizer: American Heart Association Scientific sessions 2017
  • Int'l Joint Research
• [Presentation] Novel Mechanism of High-Density Lipoprotein to Regulate 5-Lipoxygenase/Leukotriene B4 Pathway in Macrophages (2017)
  • Author(s): Tsuda S, Ishida T, et al.
  • Organizer: American Heart Association Scientific sessions 2017
  • Int'l Joint Research
• [Presentation] Cholesterol Uptake Capacity: A New Measure of HDL Functionality for Coronary Risk Stratification (2016)
  • Author(s): Amane Harada, Ryuji Toh, Katsuhiro Murakami, Maria Kiriyama, Keiko Yoshikawa, Keiko Miwa, Takuya Kubo, Yasuhiro Irino, Kenta Mori, Nobuaki Tanaka, Kunihiro Nishimura, Tatsuro Ishida, Ken-ichi Hirata
  • Organizer: 第33回 ISHR日本部会総会
  • Place of Presentation: 東京
  • Year and Date: 2016-12-16
  • Int'l Joint Research
• [Presentation] HDL粒子によるコレステロール引抜き/取込み能と冠動脈疾患との関係 (2016)
  • Author(s): Toh R,, Ishida T,Harada A, Yoshida T, Hirata K.
  • Organizer: 第64回日本心臓病学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-09-23
  • Invited
• [Presentation] Cholesterol uptake capacity, a new concept of HDL functionality, for risk stratification in coronary artery disease (2016)
  • Author(s): Toh R, Harada A, Murakami K, Kiriyama M, Yoshikawa K, Miwa K, Irino Y, Mori K, Tanaka N, Nishimura K, Ishida T, Hirata K.
  • Organizer: 68th AACC Annual Scientific Meeting & Clinical Lab Expo
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2016-08-02
  • Int'l Joint Research
• [Presentation] 高比重リポ蛋白 (HDL) の抗炎症効果はリン脂質構成に依存する (2016)
  • Author(s): Tanaka N, Irino Y, Shinohara M, Tsuda S, Nagao M, Mori K, Mori T, Hara T, Toh R, Ishida T, Hirata K.
  • Organizer: 第48回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-07-14
• [Presentation] Cholesterol Uptake Capacity, a New Measure for High-Density Lipoprotein Functionality And Its Association with Incident Cardiovascular Events. (2016)
  • Author(s): Harada A, Toh R, Murakami K, Kiriyama M, Yoshikawa K, Kubo T, Miwa K, Irino Y, Mori K, Tanaka N, Ishida T, Hirata K.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2016-03-18
• [Presentation] High-Density Lipoproteins from Coronary Artery Disease Patients Contribute to Inflammatory-prone Lipid Mediator Production. (2016)
  • Author(s): Tsuda S, Shinohara M, Irino Y, Mori K, Tanaka N, Ishida T, Hirata K.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2016-03-18
• [Presentation] HDLの抗炎症能・コレステロール引抜き能の評価方法の確立と動脈硬化における意義 (2016)
  • Author(s): Ishida T
  • Organizer: 第48回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 東京
  • Invited
• [Presentation] Serum Myeloperoxidase/Paraoxonase 1 Ratio Predicts Recurrent Coronary Artery Disease (2015)
  • Author(s): Tsuda S, Toh R, Mori K, Nagao M, Tanaka N, Mori T, Monguchi T, Nakajima H, Honjo T, Shinohara M, Nishimura K, Ishida T, Hirata K
  • Organizer: 第47回 日本動脈硬化学会総会学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2015-07-10
• [Presentation] 冠動脈疾患二次予防における予測因子としての血清ミエロペルオキシダーゼ/パラオキソナーゼ1比の有用性についての検討 (2015)
  • Author(s): Tsuda S, Toh R, Mori K, Nagao M, Tanaka N, Mori T, Monguchi T, Nakajima H, Honjo T, Shinohara M, Nishimura K, Ishida T, Hirata K
  • Organizer: 第15回日本NO学会
  • Place of Presentation: 大阪
  • Year and Date: 2015-06-26
• [Presentation] Serum myeloperoxidase/paraoxonase 1 ration predicts recurrent coronary artery disease (2015)
  • Author(s): Tsuda S, Toh R, Mori K, Nagao M, Tanaka N, Mori T, Monguchi T, Nakajima H, Honjo T, Shinohara M, Nishimura K, Ishida T, Hirata K
  • Organizer: ATVB/PVD2015
  • Place of Presentation: サンフランシスコ、アメリカ
  • Year and Date: 2015-05-08
  • Int'l Joint Research