ER stress and posttranslational modification pathways in cardiometabolic syndrome

2010 Fiscal Year Final Research Report

• 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)
• 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
• 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
  • 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] 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
• [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] 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
• [Book] The Biology of Kruppel-like Factors (2009)
  • Author(s): Manabe I
  • Total Pages: 245-252
• [Remarks]
  • URL: http://plaza.umin.ac.jp/manabe