Joseph, Christine and Berghausen, Eva Maria and Behringer, Arnica and Rauch, Bernhard H. and Ten Freyhaus, Henrik and Gnatzy-Feik, Leoni Luisa and Krause, Max and Wong, Dickson W L and Boor, Peter and Baldus, Stephan and Vantler, Marius and Rosenkranz, Stephan (2022) Coagulation-independent effects of thrombin and Factor Xa: role of protease-activated receptors in pulmonary hypertension. Cardiovascular research. pp. 1-14. ISSN 0008-6363 - 1755-3245

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Abstract

Aims: Pulmonary arterial hypertension (PAH) is a devastating disease with limited therapeutic options. Vascular remodeling of pulmonary arteries, characterized by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), is a hallmark of PAH. Here, we aimed to systematically characterize coagulation-independent effects of key coagulation proteases thrombin and factor Xa (FXa) and their designated receptors, protease-activated receptor (PAR) -1 and -2, on PASMCs in vitro and experimental PH in vivo. Methods and results: In human and murine PASMCs, both thrombin and FXa were identified as potent mitogens, and chemoattractants. FXa mediated its responses via PAR-1 and PAR-2, whereas thrombin signalled through PAR-1. Extracellular-signal regulated kinases 1/2, protein kinase B (AKT), and sphingosine kinase 1 were identified as downstream mediators of PAR-1 and PAR-2. Inhibition of FXa or thrombin blunted cellular responses in vitro, but unexpectedly failed to protect against hypoxia-induced PAH in vivo. However, pharmacological inhibition as well as genetic deficiency of both PAR-1 and PAR-2 significantly reduced vascular muscularization of small pulmonary arteries, diminished right ventricular systolic pressure, and right ventricular hypertrophy upon chronic hypoxia compared to wild-type controls. Conclusion: Our findings indicate a coagulation-independent pathogenic potential of thrombin and FXa for pulmonary vascular remodelling via acting through PAR-1 and PAR-2, respectively. While inhibition of single coagulation proteases was ineffective in preventing experimental PAH, our results propose a crucial role for PAR-1 and PAR-2 in its pathobiology, thus identifying PARs but not their dedicated activators FXa and thrombin as suitable targets for the treatment of PAH.

Item Type:	Article
Uncontrolled Keywords:	Pulmonary hypertension, Protease-activated receptors, Factor Xa, Thrombin
Subjects:	Technology, medicine, applied sciences > Medicine and health
Divisions:	Faculty of Medicine and Health Sciences > Department of Human Medicine
Date Deposited:	21 Jun 2022 12:52
Last Modified:	19 Jul 2022 08:18
URI:	https://oops.uni-oldenburg.de/id/eprint/5437
URN:	urn:nbn:de:gbv:715-oops-55183
DOI:	10.1093/cvr/cvac004
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