Effect of cPLA_2 inhibition on the prevention of diabetic macrovascular complication

• Project/Area Number: 21591144
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: MATSUMURA Takeshi 熊本大学, 医学部附属病院, 助教 (20398192)
• Co-Investigator(Kenkyū-buntansha): ARAKI Eiichi 熊本大学, 大学院・生命科学研究部, 教授 (10253733) ; KONDO Tatsuya 熊本大学, 大学院・生命科学研究部, 助教 (70398204) ; MOTOSHIMA Hiroyuki 熊本大学, 医学部附属病院, 助教 (40398201) ; 宮村 信博 熊本大学, 大学院・生命科学研究部, 准教授 (40274716)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: エネルギー・糖代謝異常 / 糖尿病大血管合併症

Research Abstract

In the present study, we investigated the mechanism(s) of PPARγ activation by inhibiting cPLA_2 on macrophages, and the anti-atherosclerotic effect of cPLA2 inhibition in macrophages and apoE-deficient mice. We revealed that cPLA_2 inhibition induced cyclooxygenase-2 expression and subsequent 15d-PGJ_2 production, resulting PPARγ activation in macrophages. Inhibition of cPLA2 suppressed LPS-induced TNF-α and MCP-1 expression, and induced ABCA1/G1 expression. Moreover, administration of cPLA_2 inhibitor, AACOCF3 suppressed the progression of atherosclerosis in apoE-deficient mice. These results suggest that cPLA2 inhibition has anti-atherosclerotic effects, and cPLA2 may be one of the therapeutic targets for diabetic macrovascular complications.

Research Products

• [Journal Article] Thiazolidinedione-independent activation of peroxisome proliferator-activated receptor is a potential target for diabetic macrovascular complications (2012)
  • Author(s): Matsumura T, Taketa K, Shimoda S, Araki E
  • Journal Title: J Diabetes Invest Volume: 3 Pages: 11-23
  • Peer Reviewed
• [Journal Article] Hyperthermia With Mild Electrical Stimulation Protects Pancreaticβ-Cells From Cell Stresses and Apoptosis (2012)
  • Author(s): Kondo T, Sasaki K, Matsuyama R, Morino-Koga S, Adachi H, Suico MA, Kawashima J, Motoshima H, Furukawa N, Kai H, Araki E
  • Journal Title: Diabetes Volume: 61 Pages: 837-847
  • Peer Reviewed
• [Journal Article] Thiazolidinedione-independent activation of peroxisome proliferator-activated recept or γ is a potential target for diabetic macrovascular complications (2012)
  • Author(s): Matsumura T
  • Journal Title: J Diabetes Invest Volume: 3 Pages: 11-23
  • Peer Reviewed
• [Journal Article] Anti-atherosclerotic Potential of Dihydropyridine Calcium Channel Blockers (2012)
  • Author(s): Ishii N
  • Journal Title: J Atheroscler Thromb Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Caloric restriction decreases ER stress in liver and adipose tissue in ob/ob mice (2011)
  • Author(s): Tsutsumi A, Motoshima H, Kondo T, Kawasaki S, Matsumura T, Hanatani S, Igata M, Ishii N, Kinoshita H, Kawashima J, Taketa K, Furukawa N, Tsuruzoe K, Nishikawa T, Araki E
  • Journal Title: Biochem Biophys Res Commun Volume: 404 Pages: 339-344
  • Peer Reviewed
• [Journal Article] Telmisartan exerts anti-atherosclerotic effects by activating PPARγin macrophages (2011)
  • Author(s): Matsumura T, Kinoshita H, Ishii N, Fukuda K, Motoshima H, Senokuchi T, Taketa K, Kawasaki S, Nishimaki-Mogami T, Kawada T, Nishikawa T, Araki E
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31 Pages: 1268-1275
  • Peer Reviewed
• [Journal Article] Angptl4 deficiency decreases serum triglyceride levels in low-density lipoprotein receptor knockout mice and streptozotocin-induced diabetic mice (2011)
  • Author(s): Adachi H, Kondo T, Koh GY, Nagy A, Oike Y, Araki E
  • Journal Title: Biochem Biophys Res Commun Volume: 409 Pages: 177-180
  • Peer Reviewed
• [Journal Article] Telmisartan exerts anti-atherosclerotic effects by activating PPARγ in macrophages (2011)
  • Author(s): Matsumura T
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31 Pages: 1268-1275
  • Peer Reviewed
• [Journal Article] Unique Roles of the p110a Isoform of Phosphoinositide 3-kinase in Hepatic Insulin Signaling and Metabolic Regulation (2010)
  • Author(s): Sopasakis VR, Liu P, Suzuki R, Kondo T, Winnay J, Tran TT, Asano T, Smyth G, Sajan MP, Farese RV, Kahn CR, Zhao JJ
  • Journal Title: Cell Metab Volume: 11 Pages: 220-230
  • Peer Reviewed
• [Journal Article] Nifedipine induces peroxisome proliferator-activated receptor-gamma activation in macrophages and suppresses the progression of atherosclerosis in apolipoprotein E-deficient mice (2010)
  • Author(s): Ishii N, Matsumura T, Kinoshita H, Fukuda K, Motoshima H, Senokuchi T, Nakao S, Tsutsumi A, Kim-Mitsuyama S, Kawada T, Takeya M, Miyamura N, Nishikawa T, Araki E
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 30 Pages: 1598-1605
  • Peer Reviewed
• [Journal Article] An Acylic Polyisoprenoid Derivative, Geranylgeranylacetone Protects Against Visceral Adiposity and Insulin Resistance in High Fat Fed Mice (2010)
  • Author(s): Adachi H, Kondo T, Ogawa R, Sasaki K, Morino-Koga S, Sakakida M, Kawashima J, Motoshima H, Furukawa N, Tsuruzoe K, Miyamura N, Kai H, Araki E
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 299
  • Peer Reviewed
• [Journal Article] The effect of group-based lifestyle interventions on risk factors and insulin resistance in subjects at risk for metabolic syndrome : the Tabaruzaka Study 1 (2010)
  • Author(s): Yamashiro T, Nishikawa T, Isami S, Wei CN, Fukumoto K, Matsuo H, Yoshinaga T, Kukidome D, Motoshima H, Matsumura T, Ueda A, Araki E
  • Journal Title: Diabetes Obes Metab Volume: 12 Pages: 790-797
  • Peer Reviewed
• [Journal Article] Nifedipine induces peroxisome proliferator-activated receptor-γ activation in macrophages and suppresses the progression of atherosclerosis in apolipoprotein E-deficient mice. (2010)
  • Author(s): Ishii N
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 30 Pages: 1598-160
  • Peer Reviewed
• [Journal Article] The effect of group-based lifestyle interventions on risk factors and insulin resistance in subjects at risk for metabolic syndrome : the Tabaruzaka Studv 1. (2010)
  • Author(s): Yamashiro T
  • Journal Title: Diabetes Obes Metab. Volume: 12 Pages: 790-797
  • Peer Reviewed
• [Journal Article] Caloric restriction decreases ER stress in liver and adipose tissue in ob/ob mice. (2010)
  • Author(s): Tsutsumi A
  • Journal Title: Biochem Biophys Res Commun. Volume: 404 Pages: 339-344
  • Peer Reviewed
• [Journal Article] TZDs reduce mitochondrial ROS production and enhance mitochondrial biogenesis (2009)
  • Author(s): Fujisawa K, Nishikawa T, Kukidome D, Imoto K, Yamashiro T, Motoshima H, Matsumura T, Araki E
  • Journal Title: Biochem Biophys Res Commun Volume: 379 Pages: 43-48
  • Peer Reviewed
• [Journal Article] Angptl 4 deficiency improves lipid metabolism, suppresses foam cell formation and protects against atherosclerosis (2009)
  • Author(s): Adachi H, Fujiwara Y, Kondo T, Nishikawa T, Ogawa R, Matsumura T, Ishii N, Nagai R, Miyata K, Tabata M, Motoshima H, Furukawa N, Tsuruzoe K, Kawashima J, Takeya M, Yamashita S, Koh GY, Nagy A, Suda T, Oike Y, Araki E
  • Journal Title: Biochem Biophys Res Commun Volume: 379 Pages: 806-811
  • Peer Reviewed
• [Journal Article] Activation of AMP-activated protein kinase suppresses oxidized low-density lipoprotein-induced macrophage proliferation (2009)
  • Author(s): Ishii N, Matsumura T, Kinoshita H, Motoshima H, Kojima K, Tsutsumi A, Kawasaki S, Yano M, Senokuchi T, Asano T, Nishikawa T, Araki E
  • Journal Title: J Biol Chem Volume: 284 Pages: 34561-34569
  • Peer Reviewed
• [Journal Article] A novel combination of mild electrical stimulation and hyperthermia : general concepts and applications (2009)
  • Author(s): Kai H, Suico MA, Morino S, Kondo T, Oba M, Noguchi M, Shuto T, Araki E
  • Journal Title: Int J Hyperthermia Volume: 25 Pages: 655-660
  • Peer Reviewed
• [Journal Article] Hypertriglyceridemic acute pancreatitis during pregnancy : prevention with diet therapy and omega-3 fatty acids in the following pregnancy (2009)
  • Author(s): Takaishi K, Miyoshi J, Matsumura T, Honda R, Ohba T, Katabuchi H
  • Journal Title: Nutrition Volume: 25 Pages: 1094-1097
  • Peer Reviewed
• [Journal Article] Activation of AMP-activated protein kinase suppresses oxidized low-density lipoprotein-induced macrophage proliferation (2009)
  • Author(s): Ishii N
  • Journal Title: J Biol Chem. 284 Pages: 34561-34569
  • Peer Reviewed
• [Journal Article] TZDs reduce mitochondrial ROS production and enhance mitochondrial biogenesis (2009)
  • Author(s): Fujisawa K
  • Journal Title: Biochem Biophys Res Commun. 379 Pages: 43-48
  • Peer Reviewed
• [Journal Article] Angptl 4 deficiency improves lipid metabolism, suppresses foam cell formation and protects against atherosclerosis (2009)
  • Author(s): Adachi H
  • Journal Title: Biochem Biophys Res Commun. 379 Pages: 806-811
  • Peer Reviewed
• [Presentation] Association of leukocyte subtype counts with carotid intima-medial thickness in Japanese subjects with type 2 diabetes (2012)
  • Author(s): 松村剛
  • Organizer: XVI International Symposium on Atherosclerosis
  • Place of Presentation: Sydney, Australia
• [Presentation] 血管構成細胞における新規PPARγ活性化機序と動脈硬化進展抑制効果 (2011)
  • Author(s): 松村剛
  • Organizer: 第26回日本糖尿病合併症学会
  • Place of Presentation: 大宮ソニックシティ,さいたま
• [Presentation] Association of circulating monocyte count with carotid intima-medial thickness in Japanese subjects with type 2 diabetes (2011)
  • Author(s): Matsumura T, Ishii N, Kinoshita H, Fukuda K, Senokuchi T, Nishikawa T, Araki E
  • Organizer: 第43回日本動脈硬化学会総会
  • Place of Presentation: ロイトン札幌,札幌
• [Presentation] 2型糖尿病における大血管合併症進展の指標としての血中単球数の有用性 (2011)
  • Author(s): 松村剛, 竹田佳代, 本島寛之, 石井規夫, 嶋田さやか, 木下博之, 福田一起, 西川武志, 荒木栄一
  • Organizer: 第54回日本糖尿病学会総会
  • Place of Presentation: さっぽろ芸術文化の館・その他,札幌
• [Presentation] 血糖指標としての血中可溶性インスリン受容体.ステロイドによる糖代謝悪化を検出できるのか?-. (2011)
  • Author(s): 本島寛之, 湯浅智之, 堤厚之, 井形元維, 近藤龍也, 河島淳司, 松村剛, 福永麻希子, 前田貴子, 川崎修二, 花谷聡子, 石井規夫, 下田誠也, 古川昇, 水流添覚, 西川武志, 蛯名洋介, 荒木栄一
  • Organizer: 第54回日本糖尿病学会総会
  • Place of Presentation: さっぽろ芸術文化の館・その他,札幌
• [Presentation] マクロファージにおける新規PPARγ活性化機序の同定と糖尿病大血管合併症抑制への応用 (2011)
  • Author(s): 松村剛, 荒木栄一
  • Organizer: 第54回日本糖尿病学会総会
  • Place of Presentation: さっぽろ芸術文化の館・その他,札幌
• [Presentation] 血管構成細胞における新規PPARγ活性化機序と動脈硬化進展抑制効果 (2011)
  • Author(s): 松村剛
  • Organizer: 第26回日本糖尿病合併症学会
  • Place of Presentation: 大宮ソニックシティ(埼玉県さいたま市)(招待講演)
• [Presentation] Association of circulating monocyte count with carotid intima-medial thickness in Japanese subjects with type 2 diabetes (2011)
  • Author(s): 松村剛
  • Organizer: 第43回日本動脈硬化学会総会
  • Place of Presentation: ロイトン札幌(札幌市)
• [Presentation] マクロファージにおける新規PPARγ活性化機序の同定と糖尿病大血管合併症抑制への応用 (2011)
  • Author(s): 松村剛
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: さっぽろ芸術文化の館(札幌市)(招待講演)
• [Presentation] 2型糖尿病における末梢血単球数とIMT肥厚度との関連 (2010)
  • Author(s): 松村剛
  • Organizer: 第48回日本糖尿病学会九州地方会
  • Place of Presentation: 大分・別府ビーコンプラザ
  • Year and Date: 2010-10-30
• [Presentation] HMG-CoA reductase inhibitors ameliorate insulin resistance trough PPAR activation (2010)
  • Author(s): 松村剛
  • Organizer: 14^<th> International Congress of Endocrinology
  • Place of Presentation: 京都、国立京都国際会館
  • Year and Date: 2010-03-30
• [Presentation] 2型糖尿病における末梢血単球数とIMT肥厚度との関連 (2010)
  • Author(s): 松村剛, 本島寛之, 竹田佳代, 石井規夫, 木下博之, 福田一起, 西川武志, 荒木栄一
  • Organizer: 第48回日本糖尿病学会九州地方会
  • Place of Presentation: 別府ビーコンプラザ,大分
• [Presentation] 短期血糖コントロール指標としての血中可溶性インスリン受容体αサブユニットの有用性 (2010)
  • Author(s): 本島寛之, 湯浅智之, 西川武志, 下田誠也, 近藤龍也, 河島淳司, 松村剛, 後藤理英子, 大久保美那, 前田貴子, 竹田佳代, 山城武司, 川崎修二, 堤厚之, 石井規夫, 久木留大介, 古川昇, 水流添覚, 宮村信博, 蛯名洋介, 荒木栄一
  • Organizer: 第53回日本糖尿病学会総会
  • Place of Presentation: ホテルグランヴィア岡山・岡山コンベンションセンター・その他,岡山
• [Presentation] HMG-CoA reductase inhibitors ameliorate insulin resistance trough PPARγactivation (2010)
  • Author(s): Matsumura T, Ishii N, Kinoshita H, Motoshima H, Murata Y, Tsuruzoe K, Nishikawa T, Araki E
  • Organizer: 14th International Congress of Endocrinology
  • Place of Presentation: Kyoto International conference center, Kyoto, Japan, Poster
• [Presentation] 新規PPARγ活性化機序の同定と糖尿病大血管合併症発症・進展抑制効果の解明 (2009)
  • Author(s): 松村剛
  • Organizer: 第47回日本糖尿病学会九州地方会
  • Place of Presentation: リーガロイヤルホテル小倉,北九州,九州ノボ賞受賞講演
• [Presentation] 血中インスリン受容体αサブユニット量は血糖コントロール指標となりえるか? (2009)
  • Author(s): 本島寛之, 西川武志, 湯浅智之, 河島淳司, 後藤理英子, 小野薫, 花谷聡子, 木下博之, 川崎修二, 堤厚之, 児島協, 松村剛, 近藤龍也, 宮村信博, 蛯名洋介, 荒木栄一
  • Organizer: 第52回日本糖尿病学会総会
  • Place of Presentation: 大阪国際会議場,大阪
• [Book] 脂質管理による合併症予防のエビデンス. Visual糖尿病臨床のすべて糖尿病合併症鑑別ポイントとベスト管理法 (2011)
  • Author(s): 松村剛
  • Publisher: 中山書店
• [Book] AMPキナーゼと動脈硬化.内分泌・糖尿病・代謝内科 (2011)
  • Author(s): 本島寛之, 松村剛, 荒木栄一
  • Publisher: 科学評論社