Cardiac Fibroblasts Play Pathogenic Roles in Idiopathic Restrictive Cardiomyopathy

  • Tsuru Hirofumi
    Department of Pediatrics, Osaka University Graduate School of Medicine
  • Ishida Hidekazu
    Department of Pediatrics, Osaka University Graduate School of Medicine
  • Narita Jun
    Department of Pediatrics, Osaka University Graduate School of Medicine
  • Ishii Ryo
    Department of Pediatrics, Osaka University Graduate School of Medicine
  • Suginobe Hidehiro
    Department of Pediatrics, Osaka University Graduate School of Medicine
  • Ishii Yoichiro
    Department of Pediatric Cardiology, Osaka Women’s and Children’s Hospital
  • Wang Renjie
    Department of Pediatrics, Osaka University Graduate School of Medicine
  • Kogaki Shigetoyo
    Department of Pediatrics, Osaka University Graduate School of Medicine Department of Pediatrics and Neonatology, Osaka General Medical Center
  • Taira Masaki
    Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine
  • Ueno Takayoshi
    Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine
  • Miyashita Yohei
    Department of Cardiology, Osaka University Graduate School of Medicine
  • Kioka Hidetaka
    Department of Cardiology, Osaka University Graduate School of Medicine
  • Asano Yoshihiro
    Department of Cardiology, Osaka University Graduate School of Medicine
  • Sawa Yoshiki
    Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine
  • Ozono Keiichi
    Department of Pediatrics, Osaka University Graduate School of Medicine

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Description

<p>Background:Restrictive cardiomyopathy (RCM) is characterized by impaired ventricular relaxation. Although several mutations were reported in some patients, no mutations were identified in cardiomyocyte expressing genes of other patients, indicating that pathological mechanisms underlying RCM could not be determined by cardiomyocytes only. Cardiac fibroblasts (CFs) are a major cell population in the heart; however, the pathological roles of CFs in cardiomyopathy are not fully understood.</p><p>Methods and Results:This study established 4 primary culture lines of CFs from RCM patients and analyzed their cellular physiology, the effects on the contraction and relaxation ability of healthy cardiomyocytes under co-culture with CFs, and RNA sequencing. Three of four patients hadTNNI3mutations. There were no significant alterations in cell proliferation, apoptosis, migration, activation, and attachment. However, when CFs from RCM patients were co-cultured with healthy cardiomyocytes, the relaxation velocity of cardiomyocytes was significantly impaired both under direct and indirect co-culture conditions. RNA sequencing revealed that gene expression profiles of CFs in RCM were clearly distinct from healthy CFs. The differential expression gene analysis identified that several extracellular matrix components and cytokine expressions were dysregulated in CFs from RCM patients.</p><p>Conclusions:The comprehensive gene expression patterns were altered in RCM-derived CFs, which deteriorated the relaxation ability of cardiomyocytes. The specific changes in extracellular matrix composition and cytokine secretion from CFs might affect pathological behavior of cardiomyocytes in RCM.</p>

Journal

  • Circulation Journal

    Circulation Journal 85 (5), 677-686, 2021-04-23

    The Japanese Circulation Society

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