Pathological mechanism of cardiac fibrosis via caveolae-related proteins in pressure-loaded heart failure

• Project/Area Number: 18K07046
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Ogata Takehiro 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10402877)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 心臓線維化 / 心不全 / 線維芽細胞 / 心筋線維化 / 線維化 / カベオラ

Outline of Final Research Achievements

To investigate the involvement of Cavin-2 in cardiac fibrosis, we generated two types of mice: systemic Cavin-2 knockout mice and fibroblast-specific Cavin-2 knockout mice. No abnormalities were observed in the development and growth of these mice. However, in a mouse model of left ventricular pressure-overloaded heart failure due to transverse aortic constriction, Cavin-2 deletion in cardiac fibroblasts resulted in marked suppression of myocardial fibrosis and cardiac dysfunction. Cardiac fibroblasts differentiate into activated myofibroblasts and promote collagen production and deposition upon TGF-β1 stimulation. Cavin-2 deletion in mouse embryonic fibroblasts suppressed TGF-β1-induced differentiation into myofibroblasts and collagen production.

Academic Significance and Societal Importance of the Research Achievements

心不全における心臓線維化は心機能に負の影響を及ぼす。線維化の制御は患者の予後改善に重要である。線維化を抑制するため、これまでにTGF-β1受容体の阻害薬を使った治療が提案されているが過度な線維化抑制による心破裂など負の影響が懸念されている。本研究でCavin-2をターゲットにした線維化制御は生理的役割を損なうことなく線維化を抑制できる可能性が示された。本研究結果は、カベオラ関連線維化シグナルの制御による心不全治療法のための基礎基盤の構築に貢献するもとの考える。

Research Products

• [Journal Article] Systems Network Genomic Analysis Reveals Cardioprotective Effect of MURC/Cavin‐4 Deletion Against Ischemia/Reperfusion Injury (2019)
  • Author(s): Nishi Masahiro、Ogata Takehiro、Cannistraci Carlo Vittorio、Ciucci Sara、Nakanishi Naohiko、Higuchi Yusuke、Sakamoto Akira、Tsuji Yumika、Mizushima Katsura、Matoba Satoaki
  • Journal Title: Journal of the American Heart Association Volume: 8 Issue: 15
  • DOI: 10.1161/jaha.119.012047
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Cavin-2 Deletion Attenuates Fibroblast Activation and Cardiac Fibrosis Via TGF-β Signaling By Interacting With Hsp90 (2020)
  • Author(s): Yusuke Higuchi, Takehiro Ogata, Naohiko Nakanishi, Akira Sakamoto, Yumika Tsuji, Shinya Tomita, Satoaki Matoba
  • Organizer: BCVS Scientific Sessions 2020
  • Int'l Joint Research
• [Presentation] Cavin-2/SDPR in Cardiac Fibroblasts Regulates Cardiac Fibrosis and Function via TGF-β/Smad Signaling in Pressure-Overloaded Hearts (2019)
  • Author(s): Yusuke Higuchi, Takehiro Ogata, Masahiro Nishi, Naohiko Nakanishi, Akira Sakamoto, Yumika Tsuji, Satoaki Matoba
  • Organizer: 2019 XXIII ISHR WORLD CONGRESS
  • Int'l Joint Research
• [Presentation] Cavin-2/SDPR in cardiac fibroblasts modulates TGF-β/Smad signaling and promotes pressure overload-induced fibrosis (2019)
  • Author(s): Yusuke Higuchi, Takehiro Ogata, Masahiro Nishi, Naohiko Nakanishi, Akira Sakamoto, Yumika Tsuji, Satoaki Matoba
  • Organizer: BCVS Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] SDPR / Cavin-2 Regulates Adipocyte Differentiation with PPARγ Expressions in 3T3L1 Cells (2019)
  • Author(s): Yusuke Higuchi, Takehiro Ogata, Masahiro Nishi, Naohiko Nakanishi, Akira Sakamoto, Yumika Tsuji, Shinya Tomita, Satoaki Matoba
  • Organizer: Cardiovascular and Metabolic Week2019(第36回国際心臓研究会日本部会総会)
• [Presentation] Cavin-2 Deficiency Attenuates Myofibroblast Differentiation and Cardiac Fibrosis in Pressure Overloaded Hearts (2019)
  • Author(s): Yusuke Higuchi, Takehiro Ogata, Masahiro Nishi, Naohiko Nakanishi, Akira Sakamoto, Yumika Tuji, Satoaki Matoba
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] Cavin-2 Deficiency Attenuates Cardiac Fibrosis and Dysfunction in Pressure-overloaded Hearts (2018)
  • Author(s): Yusuke Higuchi, Takehiro Ogata, Masahiro Nishi, Satoaki Matoba
  • Organizer: The 23rd Annual Scientific Meeting of the International Society of Cardiovascular Pharmacotherapy (ISCP)
  • Int'l Joint Research
• [Presentation] Cavin-2/SDPR Deficiency Attenuates Myofibroblast Differentiation and Cardiac Fibrosis in TAC Mice (2018)
  • Author(s): Yusuke Higuchi, Takehiro Ogata, Naohiko Nakanishi, Masahiro Nishi, Akira Sakamoto, Yumika Tsuji, Satoaki Matoba
  • Organizer: 第２回日本循環器学会基礎研究フォーラム
• [Presentation] SDPR/Cavin-2 Deficiency Attenuates Myofibroblast Differentiation via the Actin-MRTF-SRF Signaling Axis and Cardiac Fibrosis in Pressure Overload-induced Heart Failure (2018)
  • Author(s): Yusuke Higuchi, Takehiro Ogata, Masahiro Nishi, Naohiko Nakanishi, Akira Sakamoto, Yumika Tsuji, Hideo Tsubata, Satoaki Matoba
  • Organizer: The American Heart Association, Scientific Sessions 2018
  • Int'l Joint Research
• [Presentation] SDPR/Cavin-2 Deficiency Supresses Myofibroblast Differentiation via the Actin/MRTF/SRF Signaling Axis and Cardiac Fibrosis in Pressure Overload-induced Heart Failure (2018)
  • Author(s): Yusuke Higuchi, Takehiro Ogata, Masahiro Nishi, Naohiko Nakanishi, Akira Sakamoto, Yumika Tuji, Satoaki Matoba
  • Organizer: 第35回国際心臓研究学会日本部会