Protease-activated receptor 2 deficiency mediates cardiac fibrosis and diastolic dysfunction

Item Type:	Article
Title:	Protease-activated receptor 2 deficiency mediates cardiac fibrosis and diastolic dysfunction
Creators Name:	Friebel, J. and Weithauser, A. and Witkowski, M. and Rauch, B.H. and Savvatis, K. and Dörner, A. and Tabaraie, T. and Kasner, M. and Moos, V. and Bösel, D. and Gotthardt, M. and Radke, M.H. and Wegner, M. and Bobbert, P. and Lassner, D. and Tschöpe, C. and Schutheiss, H.P. and Felix, S.B. and Landmesser, U. and Rauch, U.
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.
Keywords:	Protease-Activated Receptor, Cardiac Fibroblast, Cardiac Fibrosis, Collagen, Diastolic Dysfunction, HFpEF, Animals, Mice
Source:	European Heart Journal
ISSN:	0195-668X
Publisher:	Oxford University Press
Volume:	40
Number:	40
Page Range:	3318-3332
Date:	21 October 2019
Official Publication:	https://doi.org/10.1093/eurheartj/ehz117
PubMed:	View item in PubMed

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