Julian Friebel1, Alice Weithauser1, Marco Witkowski1, Bernhard H Rauch2,3, Konstantinos Savvatis4,5, Andrea Dörner1, Termeh Tabaraie1, Mario Kasner1, Verena Moos6, Diana Bösel6, Michael Gotthardt7,8, Michael H Radke7,8, Max Wegner1, Peter Bobbert9, Dirk Lassner10, Carsten Tschöpe1, Heinz-Peter Schutheiss10, Stephan B Felix3,11, Ulf Landmesser1,8, Ursula Rauch1,8. 1. Department of Cardiology, Charité Center 11, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany. 2. Institute of Pharmacology, Center of Drug Absorption and Transport, University Medicine Greifswald, Felix-Hausdorff-Str. 3, Greifswald, Germany. 3. German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Ferdinand-Sauerbruch-Str., Greifswald, Germany. 4. Inherited Cardiovascular Diseases Unit, Barts Heart Centre, Barts Health NHS Trust, West Smithfield, London, UK. 5. William Harvey Research Institute, Queen Mary University London, Charterhouse Square, London, UK. 6. Medical Department I, Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine Berlin, Hindenburgdamm 30, Berlin, Germany. 7. Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Berlin, Robert-Rössle-Str. 10, Berlin, Germany. 8. German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Oudenarder Straße 16, Berlin, Germany. 9. Department of Internal Medicine and Angiology, Hubertus Hospital, Berlin, Spanische Allee 10-14, Berlin, Germany. 10. Institute for Cardiac Diagnostics and Therapy (IKDT), Moltkestr. 31, Berlin, Germany. 11. Department of Internal Medicine B, Cardiology, University Medicine Greifswald, Ferdinand-Sauerbruch-Str., Greifswald, Germany.
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-β)-dependent signalling. This enhanced TGF-β/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-β signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-β-axis might be a promising therapeutic approach to reduce HFpEF. Published on behalf of the European Society of Cardiology. All rights reserved.
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-β)-dependent signalling. This enhanced TGF-β/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-β signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-β-axis might be a promising therapeutic approach to reduce HFpEF. Published on behalf of the European Society of Cardiology. All rights reserved.
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