Protease-activated receptor 2 deficiency mediates cardiac fibrosis and diastolic dysfunction
| Autor: | Bernhard H. Rauch, Konstantinos Savvatis, Peter Bobbert, Ursula Rauch, Verena Moos, Carsten Tschöpe, Michael Gotthardt, Dirk Lassner, Heinz-Peter Schutheiss, Marco Witkowski, Stephan B. Felix, Termeh Tabaraie, Andrea Dörner, Alice Weithauser, Michael H. Radke, Max Wegner, Ulf Landmesser, Julian Friebel, Mario Kasner, Diana Bösel |
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| Rok vydání: | 2018 |
| Předmět: |
Male
medicine.medical_specialty Cardiac fibrosis Diastole Inflammation 030204 cardiovascular system & hematology Endothelial activation 03 medical and health sciences Mice 0302 clinical medicine Fibrosis Transforming Growth Factor beta Internal medicine medicine Animals Humans Receptor PAR-2 Protease-activated receptor 2 030304 developmental biology Aged Mice Knockout 0303 health sciences Heart Failure Diastolic business.industry Myocardium Middle Aged medicine.disease Endocrinology Myocardial fibrosis Female medicine.symptom Cardiology and Cardiovascular Medicine business Heart failure with preserved ejection fraction Cardiomyopathies |
| Zdroj: | European heart journal. 40(40) |
| ISSN: | 1522-9645 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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