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

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Item Type:	Article
Title:	Protease-activated receptor 2 deficiency mediates cardiac fibrosis and diastolic dysfunction
Creators Name:	Friebel, J., Weithauser, A., Witkowski, M., Rauch, B.H., Savvatis, K., Dörner, A., Tabaraie, T., Kasner, M., Moos, V., Bösel, D., Gotthardt, M., Radke, M.H., Wegner, M., Bobbert, P., Lassner, D., Tschöpe, C., Schutheiss, H.P., Felix, S.B., 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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