KLF6 mediated mechanism as a therapeutic target in aortic diseases

2012 Fiscal Year Final Research Report

• Project/Area Number: 23790839
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Circulatory organs internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: SAWAKI Daigo 東京大学, 医学部附属病院, 特任助教 (40456132)
• Research Collaborator: SUZUKI Toru 東京大学, 大学院・医学系研究科, 特任准教授 ; AIZAWA Kenichi 東京大学, 大学院・医学系研究科, 特任助教 ; MATSUMURA Takayoshi 東京大学, 大学院・医学系研究科, 特任助教 ; ISHIDA Zyunichi 東京大学, 医学部附属病院, 特任助教 ; 孫 輔卿 東京大学, 大学院・医学系研究科, 特任研究員 ; NAGAI Ryozo 自治医科大学, 学長
• Project Period (FY): 2011 – 2012
• Keywords: 分子血管病態学

Research Abstract

Previous studies suggest that Kruppel-like factors (KLFs) play important roles in the cardiovasculature. Preliminary studies indicated that KLF6 have roles in cardiovascular development and remodeling such as cardiac fibrosis. In this study, we next aimed to decipher the mechanism in which KLF6 mediates aortic pathologies such as aortic aneurysm or dissection. Continuous angiotensin II (AngII) infusion in klf6+/- mice resulted in decreased TGFbeta-1 expression levels both in aortic wall and serum in KLF6+/- mice, and diminished blood pressure increase (wild-type 150-160 mmHg, KLF6+/- 100-120 mmHg), which indicates possibility of blood pressure control gy KLF6 inhibition. On the other hand, KLF6+/ mice showed accelerated aortic remodeling such as inflammatory cell infiltration or MMP-2 induction and aortic walldestruction in aortic aneurysm/dissection formation with AngII + Cacl2. These data collectively showed the biphasic mechanism in aortic pathologies, indicating the importanc of meticulous decision of KLF6 targeting therapies.

Research Products

• [Journal Article] Targeting Transforming Growth Factor-β Signaling in Aortopathies in Marfan Syndrome (2013)
  • Author(s): Sawaki D, Suzuki T
  • Journal Title: Circ J Volume: 77(4) Pages: 898-9
• [Journal Article] Biomarkers of aortic diseases (2013)
  • Author(s): Suzuki T, Bossone E, Sawaki D, Janosi RA, Erbel R, Eagle K, Nagai R.
  • Journal Title: Am Heart J Volume: 165(1) Pages: 15-25
• [Journal Article] 特集『バイオマーカーupdate -診断から 治療評価へ-』「急性大動脈解離」 (2013)
  • Author(s): 澤城大悟、鈴木亨
  • Journal Title: ICUとCCU Volume: vol 37(1) Pages: 21-26
• [Journal Article] 循環器病のバイオマーカー (2012)
  • Author(s): 澤城大悟、鈴木亨
  • Journal Title: Heart View Volume: vol.16 No12(増刊号) Pages: 72-78
• [Presentation] Cardiomyocyte Regulates Cardiac Fibrosis through Cell to Cell Interaction Mediated by KLF6 (2013)
  • Author(s): Daigo Sawaki, Toru Suzuki, Kenichi Aizawa, Takayoshi Matsumura, Yoshiko Munemasa, Junichi Ishida, Scott Friedman, Komuro Issei, Ryozo Nagai
  • Organizer: 第77回日本循環器学会総会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 20130315-17
• [Presentation] KLF6 modulates aortic aneurysm formation by regulating both of inflammatory and TGFbeta signaling pathways (2013)
  • Author(s): Son BK, Suzuki T, Sawaki D, Aizawa K, Matsumura T, Munemasa Y, Zhan H, Ishida J, Scott Friedman, Komuro Issei, Nagai R
  • Organizer: 第77回日本循環器学会総会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 20130315-17
• [Presentation] Cardiomyocyte Regulates Cardiac Fibrosis through Cell to Cell Interaction Mediated by KLF6 (2012)
  • Author(s): Daigo Sawaki, Toru Suzuki, Kenichi Aizawa, Takayoshi Matsumura, Yoshiko Munemasa, Junichi Ishida, Scott Friedman, Ryozo Nagai
  • Organizer: American heart association scientific session 2012
  • Place of Presentation: Los Angeles, CA, USA
  • Year and Date: 20121105-08
• [Presentation] KLF6 Modulates Aortic Aneurysm Formation by Balancing Between Inflammatory and TGFβ Signaling Pathways FASEB Summer Research Conference (2012)
  • Author(s): Junichi Ishida, Takayoshi Matsumura, Ryozo Nagai
  • Organizer: American heart association scientific session 2012
  • Place of Presentation: Los Angeles, CA, USA
  • Year and Date: 20121105-08
• [Presentation] KLF6 in cardiovascular and metabolicdisease (2012)
  • Author(s): Suzuki T
  • Organizer: FASEB Summer Research Conference"Biology & Pathobiology of Kruppel-Like Factors (KLFs)
  • Place of Presentation: Snowmass, Colorado,USA
  • Year and Date: 20120805-09
• [Presentation] Kruppel-like Factor 6 Modulates Recruitment and Polarization of Inflammatory Cells through Cardiomyocytes in Initiation of Cardiac Fibrosis (2012)
  • Author(s): Sawaki D
  • Organizer: FASEB Summer Research Conference "Biology & Pathobiology of Kruppel-Like Factors (KLFs)
  • Place of Presentation: (Snowmass, Colorado, USA
  • Year and Date: 20120805-09
• [Presentation] Aortic remodeling stimulates aneurysm formation in apoE-/- mice through gp130/STAT3 signaling (2012)
  • Author(s): Son BK, Suzuki T, Sawaki D, Aizawa K, Matsumura T, Munemasa Y, Zhan H, Okamoto Y, Ishida J, Nagai R
  • Organizer: 第76回日本循環器学会総会・学術集会
  • Place of Presentation: 福岡
  • Year and Date: 20120316-18
• [Presentation] KLF6 Modulates Recruitment and Polarization of Inflammatory Cells through Cardiomyocytes in Initiation of Cardiac Fibrosis (2012)
  • Author(s): Daigo Sawaki, Toru Suzuki, Kenichi Aizawa, Takayoshi Matsumura, Yoshiko Munemasa, Junichi Ishida, Scott L Friedman, Ryozo Nagai
  • Organizer: 第76回日本循環器学会総会・学術集会
  • Place of Presentation: 福岡
  • Year and Date: 20120316-18
• [Remarks] 東京大学大学院医学系研究科ユビキタス予防医学講座
  • URL: http://plaza.umin.ac.jp/upm/