Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Oct 21;40(40):3318-3332.
doi: 10.1093/eurheartj/ehz117.

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

Julian Friebel  1 , Alice Weithauser  1 , Marco Witkowski  1 , Bernhard H Rauch  2   3 , Konstantinos Savvatis  4   5 , Andrea Dörner  1 , Termeh Tabaraie  1 , Mario Kasner  1 , Verena Moos  6 , Diana Bösel  6 , Michael Gotthardt  7   8 , Michael H Radke  7   8 , Max Wegner  1 , Peter Bobbert  9 , Dirk Lassner  10 , Carsten Tschöpe  1 , Heinz-Peter Schutheiss  10 , Stephan B Felix  3   11 , Ulf Landmesser  1   8 , Ursula Rauch  1   8
Affiliations

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

Julian Friebel et al. Eur Heart J. .

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: Cardiac fibroblast; Cardiac fibrosis; Collagen; Diastolic dysfunction; HFpEF; Protease-activated receptor.

PubMed Disclaimer

Comment in

Publication types