ER stress and posttranslational modification pathways in cardiometabolic syndrome

• Project/Area Number: 20390220
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: MANABBE Ichiro The University of Tokyo, 医学部附属病院, 特任准教授 (70359628)
• Co-Investigator(Kenkyū-buntansha): FUJIU Katsuhito 東京大学, 医学部附属病院, 特任助教 (30422306) ; 西村 剛 東京大学, 医学部附属病院, 特任助教 (20422305) ; 大石 由美子 東京大学, 医学部附属病院, 特任助教 (80435734)
• Co-Investigator(Renkei-kenkyūsha): NISHIMURA Go 東京大学, 医学部附属病院, 助教 (20422305)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2010: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2009: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2008: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: メタボリックシンドローム / 動脈硬化 / 転写因子 / 小胞体ストレス / 翻訳後修飾

Research Abstract

Metabolic syndrome is an clinically important risk factor for cardiovascular disease. However, it is insufficiently understood how atherosclerosis in induced in metabolic syndrome. In the present study, we analyzed molecular pathogenic mechanisms of cardiovascular and metabolic diseases in obesity. A particular focus was on the signaling and transcriptional regulatory mechanisms of vascular responses to metabolic stress, such as free fatty acids (FFAs). We found that free saturated fatty acids induce endoplasmic reticulum (ER) stress in smooth muscle cells and pancreatic ・ cells, resulting in dysfunction of those cell types. The response is mediated by TLR4. We also found that FFAs activated inflammatory processes in the heart and kidney. These results suggest that FFAs are the common factors that induce inflammatory processes in the cardiovascular, metabolic and renal systems.

Research Products

• [Journal Article] Bone marrow-derived cells contribute to vascular inflammation but do not differentiate into smooth muscle cell lineages. (2010)
  • Author(s): Iwata H, Manabe I, Fujiu K, Yamamoto T, Takeda N, Eguchi K, Furuya A, Kuro-o M, Sata M, Nagai R.
  • Journal Title: Circulation 122 Pages: 2048-2057
  • Peer Reviewed
• [Journal Article] Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. (2010)
  • Author(s): Takeda N, Manabe I, Uchino Y, Eguchi K, Matsumoto S, Nishimura S, Shindo T, Sano M, Otsu K, Snider P, Conway SJ, Nagai R.
  • Journal Title: J Clin Invest 120 Pages: 254-265
  • Peer Reviewed
• [Journal Article] Regulatory polymorphism in transcription factor KLF5 at the MEF2 element alters the response to angiotensin II and is associated with human hypertension. (2010)
  • Author(s): Oishi Y, Manabe I, Imai Y, Hara K, Horikoshi M, Fujiu K, Tanaka T, Aizawa T, Kadowaki T, Nagai R.
  • Journal Title: FASEB J 24 Pages: 1780-1788
  • Peer Reviewed
• [Journal Article] Lnk regulates integrin αIIbβ3 outside-in signaling in mouse platelets, leading to stabilization of thrombus development in vivo. (2010)
  • Author(s): Takizawa H, Nishimura S, Takayama N, Oda A, Nishikii H, Morita Y, Kakinuma S, Yamazaki S, Okamura S, Tamura N, Goto S, Sawaguchi A, Manabe I, Takatsu K, Nakauchi H, Takaki S, Eto K.
  • Journal Title: J Clin Invest 120 Pages: 179-190
  • NAID: 120003783344
  • Peer Reviewed
• [Journal Article] Regulatory polymorphism in transcription factor KLF5 at the MEF2 element alters the response to angiotensin II and is associated with human hypertension (2010)
  • Author(s): Oishi Y
  • Journal Title: FASEB Journal. Volume: 24 Pages: 1780-1788
  • Peer Reviewed
• [Journal Article] Bone marrow-derived cells contribute to vascular inflammation but do not differentiate into smooth muscle cell lineages (2010)
  • Author(s): Iwata H
  • Journal Title: Circulation Volume: 122 Pages: 2048-2057
  • Peer Reviewed
• [Journal Article] Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. (2010)
  • Author(s): Takeda N
  • Journal Title: Journal of Clinical Investigation 120 Pages: 254-265
  • Peer Reviewed
• [Journal Article] CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. (2009)
  • Author(s): Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R.
  • Journal Title: Nat Med 8 Pages: 914-920
  • Peer Reviewed
• [Journal Article] A nanoparticle system specifically designed to deliver siRNA inhibits tumor growth in vivo. (2009)
  • Author(s): Yagi N, Manabe I, Tottori T, Ishihara A, Ogata F, Kim JH, Nishimura S, Fujiu K, Oishi Y, Itaka K, Kato Y, Yamauchi M, Nagai R.
  • Journal Title: Cancer Res 69 Pages: 6531-6538
  • Peer Reviewed
• [Journal Article] FGF-2-induced HGF secretion by adipose-derived stromal cells inhibits post-injury fibrogenesis through a JNK-dependent mechanism. (2009)
  • Author(s): Suga H, Eto H, Shigeura T, Inoue K, Aoi N, Kato H, Nishimura S, Manabe I, Gonda K, Yoshimura K.
  • Journal Title: Stem Cells 27 Pages: 238-249
  • Peer Reviewed
• [Journal Article] CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. (2009)
  • Author(s): Nishimura S
  • Journal Title: Nature Medicine 15 Pages: 914-920
  • Peer Reviewed
• [Journal Article] A Nanoparticle System Specifically Designed to Deliver Short Interfering RNA Inhibits Tumor Growth In vivo. (2009)
  • Author(s): Yagi N
  • Journal Title: Cancer Research 69 Pages: 6531-6538
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): Manabe I
  • Journal Title: The Biology of Kruppel-like Factors(Springer) Pages: 245-252
• [Journal Article] SUMOylation of Kruppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-・. (2008)
  • Author(s): Oishi Y, Manabe I, Tobe K, Ohsugi M, Kubota T, Fujiu K, Maemura K, Kubota N, Kadowaki T, Nagai R.
  • Journal Title: Nat Med 14 Pages: 656-666
  • Peer Reviewed
• [Journal Article] SUMOylation of Kruppel-Like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-[delta] (2008)
  • Author(s): Oishi Y
  • Journal Title: Nature Medicine 14 Pages: 656-666
  • Peer Reviewed
• [Journal Article] Kruppe-like factor 5 causes cartilage degradation through transactivation of matrix metalloproteinase 9 (2008)
  • Author(s): Shinoda Y
  • Journal Title: Journal of Biological Chemistry 283 Pages: 24682-24689
  • Peer Reviewed
• [Presentation] Chronic inflammatory processes in metabolic syndrome and type 2 diabetes, University of Michigan Metabolism (2010)
  • Author(s): Manabe I
  • Organizer: Endocrinology and Diabetes Research Conference
  • Place of Presentation: Ann Arbor、米国
  • Year and Date: 2010-11-12
• [Presentation] Chronic inflammatory processes in metabolic syndrome and type 2 diabetes (2010)
  • Author(s): Manabe I
  • Organizer: University of Michigan Metabolism, endocrinology and diabetes research conference
  • Place of Presentation: 米国Ann Arbor
  • Year and Date: 2010-11-12
• [Presentation] Inflammation in visceral fat obesity and metabolic syndrome (2010)
  • Author(s): Manabe I
  • Organizer: International Symposium on Cardiovascular Endocrinology and Metabolism
  • Place of Presentation: 奈良
  • Year and Date: 2010-03-31
• [Presentation] Inflammation in visceral fat obesity and metabolic syndrome (2010)
  • Author(s): Manabe I
  • Organizer: International symposium on cardiovascular endocrinology and metabolism
  • Place of Presentation: 奈良
  • Year and Date: 2010-03-31
• [Presentation] Sumoylation Of Klf5 Is A Molecular Switch Regulating Ppar-delta-containing Transcriptional Programs Of Lipid Metabolism (2008)
  • Author(s): Oishi Y
  • Organizer: American Heart Association Scientific Sessions 2008
  • Place of Presentation: ニューオリンズ、米国
  • Year and Date: 2008-11-12
• [Book] 肥満の医学 (2011)
  • Author(s): 真鍋一郎
  • Total Pages: 193
  • Publisher: 日本評論社
• [Book] The Biology of Kruppel-like Factors (2009)
  • Author(s): Manabe I
• [Remarks]
  • URL: http://plaza.umin.ac.jp/manabe
• [Remarks]
  • URL: http://plaza.umin.ac.jp/manabe
• [Remarks]
  • URL: http://plaza.umin.ac.ip/manabe
• [Remarks]
  • URL: http://plaza.umin.ac.jp/manabe
• [Patent(Industrial Property Rights)] リンバ浮腫の治療法 (2010)
  • Inventor(s): 眞鍋一郎, 他
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Number: 2010-226603
  • Filing Date: 2010-10-06