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Protease-activated receptor 2 deficiency mediates cardiac fibrosis and diastolic dysfunction.
Friebel, Julian; Weithauser, Alice; Witkowski, Marco; Rauch, Bernhard H; Savvatis, Konstantinos; Dörner, Andrea; Tabaraie, Termeh; Kasner, Mario; Moos, Verena; Bösel, Diana; Gotthardt, Michael; Radke, Michael H; Wegner, Max; Bobbert, Peter; Lassner, Dirk; Tschöpe, Carsten; Schutheiss, Heinz-Peter; Felix, Stephan B; Landmesser, Ulf; Rauch, Ursula.
Afiliação
  • Friebel J; Department of Cardiology, Charité Center 11, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany.
  • Weithauser A; Department of Cardiology, Charité Center 11, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany.
  • Witkowski M; Department of Cardiology, Charité Center 11, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany.
  • Rauch BH; Institute of Pharmacology, Center of Drug Absorption and Transport, University Medicine Greifswald, Felix-Hausdorff-Str. 3, Greifswald, Germany.
  • Savvatis K; German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Ferdinand-Sauerbruch-Str., Greifswald, Germany.
  • Dörner A; Inherited Cardiovascular Diseases Unit, Barts Heart Centre, Barts Health NHS Trust, West Smithfield, London, UK.
  • Tabaraie T; William Harvey Research Institute, Queen Mary University London, Charterhouse Square, London, UK.
  • Kasner M; Department of Cardiology, Charité Center 11, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany.
  • Moos V; Department of Cardiology, Charité Center 11, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany.
  • Bösel D; Department of Cardiology, Charité Center 11, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany.
  • Gotthardt M; Medical Department I, Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany.
  • Radke MH; Medical Department I, Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany.
  • Wegner M; Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Berlin, Robert-Rössle-Str. 10, Berlin, Germany.
  • Bobbert P; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Oudenarder Straße 16, Berlin, Germany.
  • Lassner D; Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Berlin, Robert-Rössle-Str. 10, Berlin, Germany.
  • Tschöpe C; German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Oudenarder Straße 16, Berlin, Germany.
  • Schutheiss HP; Department of Cardiology, Charité Center 11, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany.
  • Felix SB; Department of Internal Medicine and Angiology, Hubertus Hospital, Berlin, Spanische Allee 10-14, Berlin, Germany.
  • Landmesser U; Institute for Cardiac Diagnostics and Therapy (IKDT), Moltkestr. 31, Berlin, Germany.
  • Rauch U; Department of Cardiology, Charité Center 11, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany.
Eur Heart J ; 40(40): 3318-3332, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31004144
ABSTRACT

AIMS:

Heart failure with preserved ejection fraction (HFpEF) and pathological cardiac aging share a complex pathophysiology, including extracellular matrix remodelling (EMR). Protease-activated receptor 2 (PAR2) deficiency is associated with EMR. The roles of PAR1 and PAR2 have not been studied in HFpEF, age-dependent cardiac fibrosis, or diastolic dysfunction (DD). METHODS AND

RESULTS:

Evaluation of endomyocardial biopsies from patients with HFpEF (n = 14) revealed that a reduced cardiac PAR2 expression was associated with aggravated DD and increased myocardial fibrosis (r = -0.7336, P = 0.0028). In line, 1-year-old PAR2-knockout (PAR2ko) mice suffered from DD with preserved systolic function, associated with an increased age-dependent α-smooth muscle actin expression, collagen deposition (1.7-fold increase, P = 0.0003), lysyl oxidase activity, collagen cross-linking (2.2-fold increase, P = 0.0008), endothelial activation, and inflammation. In the absence of PAR2, the receptor-regulating protein caveolin-1 was down-regulated, contributing to an augmented profibrotic PAR1 and transforming growth factor beta (TGF-ß)-dependent signalling. This enhanced TGF-ß/PAR1 signalling caused N-proteinase (ADAMTS3) and C-proteinase (BMP1)-related increased collagen I production from cardiac fibroblasts (CFs). PAR2 overexpression in PAR2ko CFs reversed these effects. The treatment with the PAR1 antagonist, vorapaxar, reduced cardiac fibrosis by 44% (P = 0.03) and reduced inflammation in a metabolic disease model (apolipoprotein E-ko mice). Patients with HFpEF with upstream PAR inhibition via FXa inhibitors (n = 40) also exhibited reduced circulating markers of fibrosis and DD compared with patients treated with vitamin K antagonists (n = 20).

CONCLUSIONS:

Protease-activated receptor 2 is an important regulator of profibrotic PAR1 and TGF-ß signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-ß-axis might be a promising therapeutic approach to reduce HFpEF.
Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Idioma: Inglês Revista: Eur Heart J Ano de publicação: 2019 Tipo de documento: Artigo País de afiliação: Alemanha

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Idioma: Inglês Revista: Eur Heart J Ano de publicação: 2019 Tipo de documento: Artigo País de afiliação: Alemanha