Molecular mechanisms that control stress response and tissue remodeling by cardiometabolic and immune systems

• Project/Area Number: 19209029
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: NAGAI Ryozo The University of Tokyo, 医学部附属病院, 教授 (60207975)
• Co-Investigator(Kenkyū-buntansha): MANABE Ichiro 東京大学, 医学部附属病院, 特任准教授 (70359628) ; WATANABE Masafumi 東京大学, 医学部附属病院, 助教 (60360096) ; 前村 浩二 東京大学, 医学部附属病院, 助教 (90282649)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥47,580,000 (Direct Cost: ¥36,600,000、Indirect Cost: ¥10,980,000); Fiscal Year 2009: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000); Fiscal Year 2008: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000); Fiscal Year 2007: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
• Keywords: 心不全 / 心肥大 / メタボリックシンドローム / 転写因子 / 炎症 / 動脈硬化 / 肥満 / 免疫 / KLF5 / TLR

Research Abstract

To elucidate pathogenic mechanisms underlying metabolic syndrome and cardiovascular diseases, we analyzed molecular control mechanisms of cellular stress response and gene transcription by cardiovascular, metabolic and immune systems. We focused on Toll-like receptor (TLR) signaling in metabolic stress response and Kruppel-like factor (KLF) family transcription factors in stress response and tissue remodeling in cardiovascular and metabolic tissues. We found that free fatty acids induce pathologies in both cardiovascular and metabolic systems. Moreover, we found that signaling mechanisms for ER stress, TLR, and reactive oxygen species play a role in the response to free fatty acids. We also showed that cardiac fibroblasts play a pivotal role in cardiac response to pressure overload by generating cardiac fibroblast-specific K1f5 knockout mice. Furthermore, we identified IGF-1 as an essential mediator produced by cardiac fibroblasts in the cardiac response to pressure overload. In metabolic systems, we found that KLF5 is also important for β cell dysfunction and the control of appetite.

Research Products

• [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
• [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] A Nanoparticle System Specifically Designed to Deliver Short Interfering RNA 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
• [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 15 Pages: 914-920
• [Journal Article] Kruppel-like factor 5 shows proliferation-specific roles in vascular remodeling, direct stimulation of cell growth, and inhibition of apoptosis (2009)
  • Author(s): Suzuki T, Sawaki D, Aizawa K, Munemasa Y, Matsumura T, Ishida J, Nagai R.
  • Journal Title: J Biol Chem 284 Pages: 9549-9557
• [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): Nagai R
  • Journal Title: The Biology of Kruppel-like Factors(Springer) Pages: 3-18
• [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, 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
• [Journal Article] In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue (2008)
  • Author(s): Nishimura S, Manabe I, Nagasaki M, Seo K, Yamashita H, Hosoya Y, Ohsugi M, Tobe K, Kadowaki T, Nagai R, Sugiura S.
  • Journal Title: J Clin Invest 118 Pages: 710-721
• [Journal Article] Kruppel-like factor 5 causes cartilage degradation through transactivation of matrix metalloproteinase 9 (2008)
  • Author(s): Shinoda Y, Ogata N, Higashikawa A, Manabe I, Shindo T, Yamada T, Kugimiya F, Ikeda T, Kawamura N, Kawasaki Y, Tsushima K, Takeda N, Nagai R, Hoshi K, Nakamura K, Chung UI, Kawaguchi H.
  • Journal Title: J Biol Chem 283 Pages: 24682-24689
• [Journal Article] Klf5 is involved in self-renewal of mouse embryonic stem cells (2008)
  • Author(s): Parisi S, Passaro F, Aloia L, Manabe I, Nagai R, Pastore L, Russo T.
  • Journal Title: J Cell Sci 121 Pages: 2629-2634
• [Journal Article] Promoter region-specific histone incorporation by the novel historic chaperone ANP32B and DNA-binding factor KLF5 (2008)
  • Author(s): Munemasa Y, Suzuki T, Aizawa K, Miyamoto S, Imai Y, Matsumura T, Horikoshi M, Nagai R.
  • Journal Title: Mol Cell Biol 28 Pages: 1171-1181
• [Journal Article] Genetic variations of Mrf-2/ARID5B confer risk of coronary atherosclerosis in the Japanese population (2008)
  • Author(s): Wang G, Watanabe M, Imai Y, Hara K, Manabe I, Maemura K, Horikoshi M, Kohro T, Amiya E, Sugiyama T, Fujita T, Kadowaki T, Yamazaki T, Nagai R.
  • Journal Title: Int Heart J 49 Pages: 313-327
  • NAID: 130000069020
• [Journal Article] SUMOylation of Kruppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolisminvolving PPAR-[delta] (2008)
  • Author(s): Oishi Y
  • Journal Title: Nature Medicne 14 Pages: 656-666
  • Peer Reviewed
• [Journal Article] Kruppel-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
• [Journal Article] Klf5 is involved in self-renewal of mouse embryonic stem cells (2008)
  • Author(s): Parisi S
  • Journal Title: Journal of Cell Science 121 Pages: 2629-2634
  • Peer Reviewed
• [Journal Article] In vivo imaging revealed local cell dynamics in obese adipose tissue inflammationJ Clin Invest (2008)
  • Author(s): Nishimura S
  • Journal Title: Takeda N 118 Pages: 710-721
  • Peer Reviewed
• [Journal Article] Promoter region-specific histone incorporation by the novel histonechaperone ANP32B and DNA-binding factor KLF5 (2008)
  • Author(s): Munemasa Y
  • Journal Title: Mol Cell Biol 28 Pages: 1171-1181
  • Peer Reviewed
• [Journal Article] Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels (2007)
  • Author(s): Nishimura S, Manabe I, Nagasaki M, Hosoya Y, Yamashita H, Fujita H, Ohsugi M, Tobe K, Kadowaki T, Nagai R, Sugiura S.
  • Journal Title: Diabetes 56 Pages: 1517-1526
• [Journal Article] Thrombomodulin is a clock-controlled gene in vascular endothelial cells (2007)
  • Author(s): Takeda N, Maemura K, Horie S, Oishi K, Imai Y, Harada T, Saito T, Shiga T, Amiya E, Manabe I, Ishida N, Nagai R.
  • Journal Title: J Biol Chem 282 Pages: 32561-32567
• [Journal Article] Acyclic retinoid inhibits neointima formation through retinoic acid receptor beta-induced apoptosis (2007)
  • Author(s): Kada N, Suzuki T, Aizawa K, Matsumura T, Ishibashi N, Suzuki N, Takeda N, Munemasa Y, Sawaki D, Ishikawa T, Nagai R.
  • Journal Title: Arterioscler Thromb Vasc Biol 27 Pages: 1535-1541
• [Journal Article] Thrombomodulin Is a Clock-controlled Gene in Vascular Endothelial Cells (2007)
  • Author(s): Takeda N
  • Journal Title: J Biol Chem 282 Pages: 32561-32567
  • 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
  • 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 (in press)
• [Presentation] Jokichi Takamine Memorial Award (2010)
  • Author(s): Nagai R
  • Organizer: International symposium on cardiovascular endocrinology and metabolism
  • Place of Presentation: 奈良
  • Year and Date: 2010-03-31
• [Presentation] (2010)
  • Author(s): Nagai R
  • Organizer: 14th International Congress of Endocrinology "Interplay among the vascular, metabolic and immune systems in cardiovascular remodeling and metabolic syndrome
  • Place of Presentation: 京都
  • Year and Date: 2010-03-28
• [Presentation] Cardiovascular remodeling and energy metabolism through Kruppel-like transcription factor 5 (2009)
  • Author(s): Nagai R
  • Organizer: 15th International Symposium on Atherosclerosis, Workshop 4 : Workshop 4.8
  • Place of Presentation: Boston
  • Year and Date: 2009-06-16
• [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
• [Presentation] KLF5, a key transcriptional factor when regulates SMC phenotypic modulation and metabolic syndrome (2008)
  • Author(s): Nagai R
  • Organizer: 15th International Vascular Biology Meeting, Plenary Session 3
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2008-06-02
• [Presentation] Significance of the transcription factor KLF5 in myocardial hypertrophy inresponse to pressure overload (2008)
  • Author(s): Takeda N
  • Organizer: 第72回日本循環器学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2008-03-29
• [Presentation] Significance of Kruppel-Like Transcription Factor 5 in Cardiovascular Disease (2007)
  • Author(s): Nagai R
  • Organizer: The Joint Meeting of Vascular Biology Organization in Asia Pacific Region
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2007-10-20
• [Book] The Biology of Kruppel-like Factors (2009)
  • Author(s): Nagai R, Friedman J, Kasuga M, 編集
  • Total Pages: 258
  • Publisher: Springer
• [Book] Kruppel-like Factors : Ingenious Three Fingers Directing Biology and Pathobiology in The Biology of Kruppel-like (2009)
  • Author(s): Nagai R, Manabe I, Suzuki T.
• [Book] Drug development and Kruppel-like factors in The Biology of Kruppel-like Factors (2009)
  • Author(s): Manabe I, Nagai R.
• [Remarks]
  • URL: http://plaza.umin.ac.jp/nagai
• [Remarks]
  • URL: http://plaza.umin.ac.jp/nagai
• [Remarks]
  • URL: http://plaza.umin.ac.jp/nagai
• [Remarks]
  • URL: http://plaza.umin.ac.jp/nagai